CN1893954A - [2-(8,9-dioxo-2,6-diazabicyclo[5.2.0]non-1(7)-en(EN)-2-yl)alkyl]phosphoric acid and its derivatives oral administration - Google Patents

Abstract

Solid pharmaceutical dosage forms of [ 2- (8, 9-dioxo-2, 6-diazabicyclo [5.2.0] non-1 (7) -en-2-yl) alkyl ] phosphoric acid and derivatives thereof are disclosed. In addition, methods for treating cerebrovascular disorders, anxiety disorders; mood disorders; schizophrenia; schizophreniform disorder; schizoaffective disorder; cognitive impairment; chronic neurodegenerative diseases, inflammatory diseases; fibromyalgia; herpes zoster complications, prevention of tolerance to opiate analgesia; withdrawal symptoms of addictive drugs; and methods of use for pain.

Description

[2-(8,9-dioxo-2,6-diazabicyclo[5.2.0]non-1(7)-en(EN)-2-yl)alkyl]phosphoric acid and its derivatives oral administration

Cross References to Related Applications

[0001] The application requires the priority of the U.S. application No. ___ submitted on October 8, 2004, and the U.S. application No. 60/511, the rights and interests of No. 560 submitted on October 15, 2003, and its entire disclosure is incorporated herein Reference. This application is related to co-pending U.S. Application No. 10/820,215, filed April 7, 2004, and co-pending U.S. Application No. 10/820,216, filed April 7, 2004, the entire disclosures of which are incorporated herein as refer to.

technical field

The present invention relates to [2-(8,9-dioxo-2,6-diazabicyclo[5.2.0]non-1(7)-en-2-yl)alkyl]phosphoric acid and its Solid pharmaceutical dosage forms of derivatives and methods of use thereof.

Background technique

[0003] Much preclinical and clinical evidence suggests that inhibitors of N-methyl-D-aspartate (NMDA) receptors have therapeutic potential for the treatment of many conditions. Diseases thought to be responsive to NMDA receptor inhibition include cerebrovascular diseases such as cerebral ischemia (e.g., stroke) or cerebral infarction, or cerebral vasospasm, which can lead to a range of conditions such as thromboembolic or hemorrhagic stroke; brain trauma; muscle Convulsions; and convulsive disorders such as epilepsy or status epilepticus. NMDA receptor antagonists can also be used to prevent resistance to opioid analgesics or to help control withdrawal symptoms of addictive drugs.

[0004] Compound screening in recent years has identified a number of NMDA receptor antagonists that have been used in animal and human clinical studies to demonstrate proof of concept for the treatment of a variety of diseases. The difficulty presented by the clinical use of NMDA receptor antagonists is often the lack of selectivity and/or biological activity of the antagonists for NMDA receptor subtypes when administered orally.

[2-(8,9-dioxo-2,6-diazabicyclo [5.2.0] non-1 (7)-en-2-yl) alkyl] phosphoric acid and derivatives thereof have been Shown utility as NMDA receptor antagonist. See for example US-A-5,168,103 and WO03/031,416, the entire disclosures of which are incorporated herein by reference. This compound is very soluble in the pH range of 4 to 8. The apparent octanol/lipid-water partition coefficient is low (log partition coefficient -1.37) and is poorly permeable to Caco-2 cells, thus showing low and incomplete oral absorption. Based on its high solubility and low permeability, [2-(8,9-dioxo-2,6-diazabicyclo[5.2.0]non-1(7)-en-2-yl) Alkyl]phosphoric acid is classified as BCSClass 3. Animal absorption studies show that the compound has a bioavailability of about 1% at a dose of 100 mg/kg in rats and about 2.5% in monkeys at a dose of 100 mg/kg. Low bioavailability in this range may increase the dosage and cost of this product. In addition, in humans there may also be an issue of inter-subject variability in plasma levels, which may be further complicated by absorption effects from food.

[2-(8,9-dioxo-2,6-diazabicyclo[5.2.0]non-1(7)-en-2-yl)alkyl]phosphoric acid is crystal powder, has Extremely low bulk density, poor flow and compressibility, leading to problems in the preparation of capsules or tablets by dry blending methods, including mixture segregation, poor content uniformity, and fill weight variability. Even the inclusion of directly compressible excipients does not solve these problems, especially when it is desired that the active pharmaceutical ingredient constitutes a significant proportion of the formulation, for example, greater than about 70% by weight, based on the total weight of the formulation. Also, since this compound has an extremely low bulk density, it was filled with 300 mg of [2-(8,9-dioxo-2,6-diazabicyclo [5.2.0] The formulation of non-1(7)-en-2-yl)alkyl]phosphoric acid or its derivatives is difficult.

Summary of the invention

The present invention provides and comprises [2-(8,9-dioxo-2,6-diazabicyclo[5.2.0] non-1(7)-en-2-yl) alkyl] phosphoric acid Pharmaceutical compositions and dosage forms of derivatives thereof. We have unexpectedly found that this composition exhibits improved oral bioavailability.

[0008] In one embodiment, the present invention relates to solid pharmaceutical dosage forms comprising:

At least one compound of formula (I) or a pharmaceutically acceptable salt thereof:

in:

R ₁ is hydrogen, C ₁ to C ₆ alkyl, C ₂ to C ₇ acyl, C ₁ to C ₆ alkylsulfonyl (alkanes-ulfonyl), or C ₆ to C ₁₄ aroyl;

A is an alkylene group (alkylenyl) of 1 to 4 carbon atoms or an alkenylene group (alkenylenyl) of 2 to 4 carbon atoms;

R ₂ and R ₃ are independently selected from hydrogen,

with the proviso that at least one of _R2 and _R3 is not hydrogen;

R ₄ and R ₅ are independently selected from hydrogen, C ₁ to C ₄ alkyl, C ₅ to C ₇ aryl, C ₆ to C ₁₅ aralkyl having 5 to 7 carbon atoms on the aromatic ring, C ₂ to C ₇ alkenyl, or C ₂ to C ₇ alkynyl, or R ₄ and R ₅ can jointly form a spiro C ₃ to C ₈ carbocycle;

R ₆ is C ₁ to C ₁₂ linear or branched alkyl, C ₂ to C ₇ linear or branched alkenyl or alkynyl, C ₅ to C ₁₃ aryl, with _C6 to _C21 aralkyl of 5 to 13 carbon atoms, 5 to 13 membered heteroaryl, 6 to 21 membered heteroaralkyl having 5 to 13 atoms on the heteroaryl part , C ₄ to C ₈ cycloalkyl, C ₅ to C ₁₆ cycloalkylalkyl having 4 to 8 carbon atoms in the cycloalkyl ring;

R ₇ and R ₈ are independently selected from hydrogen, C ₁ to C ₁₂ straight or branched chain alkyl, C ₂ to C ₇ straight or branched alkenyl or alkynyl, C ₅ to C ₁₃ Aryl, _C6 to _C21 aralkyl having 5 to 13 carbon atoms in the aryl part, 5- to 13-membered heteroaryl, 6- to 13-membered heteroaryl having 5 to 13 atoms in the heteroaryl part A 21-membered heteroarylalkyl group, or _R7 and _R8 may together form a cycloalkyl or heterocyclic ring having 4 to 8 carbon atoms in the ring and optionally one or two atoms selected from nitrogen, oxygen or sulfur alkyl;

wherein the _R to R groups having an aryl, heteroaryl, cycloalkyl or _{heterocycloalkyl} moiety can optionally be replaced by 1 to about 5 substituents independently selected from halogen, cyano, nitro or hydroxyl, _C1 to _C6 alkyl, _C1 to _C6 alkoxy; and

at least one pharmaceutically acceptable absorption enhancer.

[0009] In another embodiment, the present invention relates to a solid pharmaceutical dosage form, comprising: at least one compound of general formula (I) or a pharmaceutically acceptable salt thereof:

in:

_R1 is hydrogen;

A is -(CH ₂ ) _n -, n is 2; and

R _{and R} are hydrogen; and

at least one pharmaceutically acceptable absorption enhancer.

[0010] In another embodiment, the present invention relates to a method of treating in a mammal at least one condition selected from cerebrovascular disease selected from cerebral ischemia, cerebral infarction or cerebral vasospasm; traumatic brain injury; Muscle spasm; convulsive disorder selected from epilepsy or status epilepticus; hypoglycemia; cardiac arrest; asphyxial anoxia; or spinal cord injury, comprising the steps of:

An effective amount of the above solid pharmaceutical dosage form is orally administered to a mammal in need thereof.

[0011] In another embodiment, the present invention relates to a method for treating at least one disease selected from glaucoma or diabetic end-organ complications in a mammal, comprising the steps of:

An effective amount of the above solid pharmaceutical dosage form is orally administered to a mammal in need thereof.

In another embodiment, the present invention relates to the treatment of at least one selected from anxiety disorders; mood disorders; schizophrenia; schizophrenia-like disorders; or schizoaffective disorders in mammals method, including the steps of:

An effective amount of the above solid pharmaceutical dosage form is orally administered to a mammal in need thereof.

In another embodiment, the present invention relates to the treatment of at least one selected from Huntington's disease, Alzheimer's disease, amyotrophic lateral sclerosis, chronic dementia, or cognitive impairment in mammals A method for a neurodegenerative disease comprising the steps of:

An effective amount of the above solid pharmaceutical dosage form is orally administered to a mammal in need thereof.

In another embodiment, the present invention relates to the method for the treatment of Parkinson's disease,

Include steps:

An effective amount of the above solid pharmaceutical dosage form is orally administered to a mammal in need thereof.

[0015] In another embodiment, the present invention relates to a prophylactic or addictive drug for the treatment of at least one selected from the group consisting of inflammatory diseases; fibromyalgia; herpes zoster complications; tolerance to opiate analgesics in mammals A method for a disorder of withdrawal symptoms comprising the steps of:

An effective amount of the above solid pharmaceutical dosage form is orally administered to a mammal in need thereof.

[0016] In another embodiment, the present invention relates to a method of treating pain in a mammal, comprising the steps of:

An effective amount of the above solid pharmaceutical dosage form is orally administered to a mammal in need thereof.

[0017] In another embodiment, the present invention relates to solid, immediate release pharmaceutical compositions comprising:

At least one compound of formula (I) or a pharmaceutically acceptable salt thereof:

in:

R ₁ is hydrogen, C ₁ to C ₆ alkyl, C ₂ to C ₇ acyl, C ₁ to C ₆ alkanesulfonyl or C ₆ to C ₁₄ aroyl;

A is an alkylene group of 1 to 4 carbon atoms or an alkenylene group of 2 to 4 carbon atoms;

R _{and R} are independently selected from hydrogen,

with the proviso that at least one of R _{and R} is not hydrogen;

R ₄ and R ₅ are independently selected from hydrogen, C ₁ to C ₄ alkyl, C ₅ to C ₇ aryl, C ₆ to C ₁₅ aralkyl having 5 to 7 carbon atoms in the aromatic ring , C ₂ to C ₇ alkenyl, or C ₂ to C ₇ alkynyl, or R ₄ and R ₅ can jointly form a spiro C ₃ to C ₈ carbocycle;

R ₆ is C ₁ to C ₁₂ linear or branched alkyl, C ₂ to C ₇ linear or branched alkenyl or alkynyl, C ₅ to C ₁₃ aryl, with _C6 to _C21 aralkyl groups of 5 to 13 carbon atoms, 5 to 13 membered heteroaryl groups, 6 to 21 membered heteroaralkyl groups having 5 to 13 atoms in the heteroaryl part, C ₄ to C ₈ cycloalkyl, C ₅ to C ₁₆ cycloalkylalkyl having 4 to 8 carbon atoms on the cycloalkyl ring;

R ₇ and R ₈ are independently selected from hydrogen, C ₁ to C ₁₂ straight or branched chain alkyl, C ₂ to C ₇ straight or branched alkenyl or alkynyl, C ₅ to C ₁₃ Aryl, a _C6 to _C21 aralkyl group having 5 to 13 carbon atoms in the aryl part, a 5- to 13-membered heteroaryl group, a 6- to 6-membered heteroaryl group having 5 to 13 atoms in the heteroaryl part A 21-membered heteroarylalkyl group, or _R7 and _R8 may together form a cycloalkyl or heteroalkyl group having 4 to 8 carbon atoms in the ring and optionally one to two atoms selected from nitrogen, oxygen or sulfur Cycloalkyl;

Any of the R _{to R} groups having an aryl, heteroaryl, cycloalkyl or heterocycloalkyl moiety may optionally be in the aryl, heteroaryl, cycloalkyl or heterocycloalkyl moiety Substituted by 1 to about 5 substituents independently selected from halogen, cyano, nitro or hydroxyl, _C1 to _C6 alkyl, _C1 to _C6 alkoxy;

wherein the above composition has a bulk density of at least about 0.5 g/cm ³ .

[0018] In another embodiment, the present invention relates to solid immediate release pharmaceutical compositions comprising:

At least one compound of formula (I) or a pharmaceutically acceptable salt thereof:

in:

_R1 is hydrogen;

A is -(CH ₂ ) _n -, n is 2; and

R _{and R} are hydrogen; and

wherein the above composition has a bulk density of at least about 0.5 g/cm ³ .

[0019] In other embodiments, the invention is directed to single dosage forms. In other embodiments, the invention relates to multiple dosage forms.

[0020] In a further embodiment, the invention relates to capsules. In a further embodiment, the present invention also relates to tablets.

[0021] In another embodiment, the present invention relates to a method comprising the steps of:

A wet granule is formed which includes:

at least one adhesive;

optionally at least one filler;

optionally at least one disintegrant; and

at least one compound of formula (I) or a pharmaceutically acceptable salt thereof; and

Form a solid dosage form.

[0022] In another embodiment, the present invention is directed to a product prepared by the method described above.

Brief description of the drawings

Fig. 1 is receiving 200,400,800 or 1600mg of [2-(8,9-dioxo-2,6-diazabicyclo[5.2.0]non-1(7)-ene- The average single dose of [2-(8,9-dioxo-2,6-diazabicyclo[5.2.0 ]Non-1(7)-en-2-yl)alkyl]phosphate mean plasma concentration (ng/mL) curve.

Fig. 2 is receiving 200,400,800, or [2-(8,9-dioxo-2,6-diazabicyclo[5.2.0]non-1(7)-ene of 1600mg A single dose of [2-(8,9-dioxo-2,6-diazabicyclo[5.2.0 C _max (ng/mL) curve of ]non-1(7)-en-2-yl)alkyl]phosphoric acid.

Fig. 3 is receiving 200,400,800, or [2-(8,9-dioxo-2,6-diazabicyclo[5.2.0]non-1(7)-ene of 1600mg A single dose of [2-(8,9-dioxo-2,6-diazabicyclo[5.2.0 AUC (ng·h/mL, t=0 to ∞) curve of ]non-1(7)-en-2-yl)alkyl]phosphoric acid.

Fig. 4 is receiving 200,400,800, or [2-(8,9-dioxo-2,6-diazabicyclo[5.2.0]non-1(7)-ene of 1600mg [2-(8,9-dioxo-2,6-diazabicyclo[5.2.0]nonane- Mean steady-state plasma concentration (ng/mL) profile of 1(7)-en-2-yl)alkyl]phosphate.

Fig. 5 is receiving 200,400,800, or [2-(8,9-dioxo-2,6-diazabicyclo[5.2.0]non-1(7)-ene of 1600mg [2-(8,9-dioxo-2,6-diazabicyclo[5.2.0]nonane- Steady-state C _max (ng/mL) curve of 1(7)-en-2-yl)alkyl]phosphoric acid.

Fig. 6 accepts 200,400,800, or [2-(8,9-dioxo-2,6-diazabicyclo[5.2.0]non-1(7)-ene- [2-(8,9-dioxo-2,6-diazabicyclo[5.2.0]nonan-1 as a function of dose (mg) after 2-yl)alkyl]phosphate in healthy subjects Steady-state AUC (ng·h/mL, t=0 to tau (12 hours)) curve of (7)-en-2-yl)alkyl]phosphoric acid.

Detailed description of the invention

[0029] As used above and throughout this disclosure, the following terms, unless otherwise indicated, shall be understood to have the following meanings.

As used herein, "alkyl" refers to an aliphatic hydrocarbon group with 1 to 12 carbon atoms, including but not limited to straight or branched chains such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, and isohexyl. "Lower alkyl" refers to an alkyl group having 1 to 3 carbon atoms.

As used herein, "alkylene" refers to an aliphatic hydrocarbon diradical with 1 to 12 carbon atoms, including but not limited to linear or branched chains such as methylene, ethylene, normal Propyl, isopropylene, n-butylene, isobutylene, sec-butylene, tert-butylene, n-pentylene, isopentylene, neopentylene, n-hexylene, and isohexylene. "Lower alkylene" refers to an alkylene group having 1 to 3 carbon atoms.

[0032] As used herein, "alkenyl" refers to a straight or branched chain hydrocarbon group having 2 to 7 carbon atoms containing 1 to 3 double bonds. Examples of alkenyl groups are linear or branched mono-, di-, or polyunsaturated groups such as vinyl, prop-1-enyl, allyl, methallyl, but-1-enyl , but-2-enyl and but-3-enyl.

[0033] As used herein, "alkenylene" refers to an aliphatic straight or branched hydrocarbon diradical having 2 to 7 carbon atoms containing 1 to 3 double bonds. Examples of alkenylene are linear or branched mono-, di-, or polyunsaturated groups such as ethenylene, prop-1-enylenyl, allyl, methylene allyl group, but-1-enylene, but-2-enylene and but-3-enylene.

[0034] As used herein, "alkynyl" refers to an aliphatic straight or branched hydrocarbon chain having 2 to 7 carbon atoms containing 1 to 3 triple bonds.

[0035] As used herein, "acyl" refers to the group RC(=O)-, wherein R is an alkyl group of 1 to 5 carbon atoms. For example, a C ₂ to C ₇ acyl group refers to a RC(=O)- group, where R is an alkyl group of 1 to 6 carbon atoms.

[0036] As used herein, "alkanesulfonyl" refers to RS(O) _2- , wherein R is an alkyl group of 1 to 6 carbon atoms.

[0037] As used herein, "aryl" refers to an aromatic 5- to 13-membered monocarbocycle or bicarbocycle such as phenyl or naphthyl. Preferably, the group comprising an aryl moiety is a monocyclic ring having 5 to 7 carbon atoms in the ring. As used herein, "heteroaryl", (Het Ar) refers to an aromatic monocyclic or bicyclic ring containing 5 to 13 carbon atoms having one to five heteroatoms independently selected from nitrogen, oxygen or sulfur. Preferably, the group comprising a heteroaryl moiety is a monocyclic ring having 5 to 7 atoms in the ring, of which one to two ring members are independently selected from nitrogen, oxygen or sulfur. Groups containing aryl or heteroaryl moieties may optionally be substituted or unsubstituted as defined below.

[0038] As used herein, "aroyl" refers to the group Ar-C(=O)-, wherein Ar is aryl as defined above. For example, a _C6 to _C14 aroyl moiety refers to the group Ar-C(=O)-, where Ar is an aromatic 5- to 13-membered carbocyclic ring.

[0039] As used herein, "aralkyl" refers to a group -R-Ar, wherein Ar is an aryl group as defined above, and R is a carbon having 1 to 8, preferably 1 to 6, more preferably 1 to 4 carbon atoms Alkylene moiety. Examples of aralkyl groups include benzyl, phenethyl, 3-phenylpropyl, and 4-phenylbutyl.

[0040] As used herein, "heteroaralkyl" refers to the group -R-hetAr, wherein hetAr is a heteroaryl as defined above, R is a group having 1 to 8, preferably 1 to 6, more preferably 1 to 4 carbon The alkylene portion of the atom.

[0041] As used herein, "cycloalkyl" refers to a single carbocyclic ring having from 3 to 8 carbon atoms. Groups comprising cycloalkyl groups are optionally substituted or unsubstituted as defined below.

[0042] As used herein, "heterocycloalkyl" refers to a monocarbocyclic ring having 3 to 8 ring members, of which one to two ring atoms are independently selected from nitrogen, oxygen or sulfur. Groups containing heterocycloalkyl moieties are optionally substituted or unsubstituted as defined below.

[0043] As used herein, "cycloalkylalkyl" refers to the group -R-cycloalk, wherein cycloalk is cycloalkyl as defined above, and R is a cycloalkyl group having 1 to 8, preferably 1 to 6, and more preferably 1 to 4 an alkylene moiety of carbon atoms.

[0044] As used herein, "halogen" refers to fluorine, chlorine, bromine or iodine.

[0045] As used herein, "pharmaceutically acceptable" refers to a substance suitable for use in pharmaceutical applications from a toxicological point of view and which does not adversely interact with the active ingredient.

As used herein, "substituted" means that a moiety such as an aryl, heteroaryl, cycloalkyl or heterocycloalkyl moiety has 1 to about 5 substituents, more preferably 1 to about 3 substituents, The substituents are independently selected from halogen, cyano, nitro or hydroxyl, C ₁ to C ₆ alkyl, or C ₁ to C ₆ alkoxy. Preferred substituents are halogen, hydroxyl, or C ₁ to C ₆ alkyl.

[0047] " _Cmax ", " _Tmax ", and "AUC" values reported herein, unless indicated as "mean values", refer to observed values in a single patient. Also, unless otherwise stated, " _Cmax ,"" _Tmax ," and "AUC" values may be those observed at steady state when administered at regular intervals (e.g., every 12 hours) over multiple days (e.g., multiple dose administration). The value of or may be the value observed when a single dose is administered.

[0048] Accordingly, in one embodiment, the invention provides a solid pharmaceutical dosage form comprising:

At least one compound of formula (I) or a pharmaceutically acceptable salt thereof:

in:

R ₁ is hydrogen, C ₁ to C ₆ alkyl, C ₂ to C ₇ acyl, C ₁ to C ₆ alkanesulfonyl, or C ₆ to C ₁₄ aroyl;

A is an alkylene group of 1 to 4 carbon atoms or an alkenylene group of 2 to 4 carbon atoms;

R _{and R} are independently selected from hydrogen,

with the proviso that at least one of R _{and R} is not hydrogen;

R _and R are _{independently} selected from hydrogen, C _to C alkyl, C to _C aryl, C to _C aralkyl having _{5 to 7} carbon atoms in the aromatic ring, C ₂ to C ₇ alkenyl, or C ₂ to C ₇ alkynyl, or R ₄ and R ₅ can jointly form a spiro C ₃ to C ₈ carbocycle.

R ₆ is C ₁ to C ₁₂ linear or branched alkyl, C ₂ to C ₇ linear or branched alkenyl or alkynyl, C ₅ to C ₁₃ aryl, with C ₆ to C ₂₁ aralkyl groups of 5 to 13 carbon atoms; 5 to 13 membered heteroaryl groups, 6 to 21 membered heteroaralkyl groups having 5 to 13 atoms in the heteroaryl part, C ₄ to C ₈ cycloalkyl, C ₅ to C ₁₆ cycloalkylalkyl having 4 to 8 carbon atoms on the cycloalkyl;

R ₇ and R ₈ are independently selected from hydrogen, C ₁ to C ₁₂ straight or branched chain alkyl, C ₂ to C ₇ straight or branched alkenyl or alkynyl, C ₅ to C ₁₃ Aryl, a _C6 to _C21 aralkyl group having 5 to 13 carbon atoms in the aryl part, a 5- to 13-membered heteroaryl group, a 6- to 6-membered heteroaryl group having 5 to 13 atoms in the heteroaryl part A 21-membered heteroarylalkyl group, or _R7 and _R8 may together form a cycloalkyl or heterocyclic ring having 4 to 8 carbon atoms in the ring and optionally one to two atoms selected from nitrogen, oxygen or sulfur alkyl;

wherein any of the R _{to R} groups having an aryl, heteroaryl, cycloalkyl or heterocycloalkyl moiety may optionally be present in the aryl, heteroaryl, cycloalkyl or heterocycloalkyl moiety substituted by 1 to about 5 substituents independently selected from halogen, cyano, nitro or hydroxy, _C to C _alkyl , or _C to C _alkoxy ; and

at least one pharmaceutically acceptable absorption enhancer.

[0049] In another embodiment, the present invention relates to solid pharmaceutical dosage forms comprising:

At least one compound of formula (I) or a pharmaceutically acceptable salt thereof:

in:

_R1 is hydrogen;

A is -(CH ₂ ) _n -, where n is 2; and

R _{and R} are hydrogen; and

at least one pharmaceutically acceptable absorption enhancer.

[0050] In another embodiment, the present invention relates to solid immediate release pharmaceutical compositions comprising:

At least one compound of formula (I) or a pharmaceutically acceptable salt thereof:

in:

R ₁ is hydrogen, C ₁ to C ₆ alkyl, C ₂ to C ₇ acyl, C ₁ to C ₆ alkanesulfonyl, or C ₆ to C ₁₄ aroyl;

A is an alkylene group of 1 to 4 carbon atoms or an alkenylene group of 2 to 4 carbon atoms;

R _{and R} are independently selected from hydrogen,

with the proviso that at least one of R _{and R} is not hydrogen;

R _and R are _{independently} selected from hydrogen, C _to C alkyl, C to _C aryl, C to _C aralkyl having _{5 to 7} carbon atoms in the aromatic ring, C ₂ to C ₇ alkenyl, or C ₂ to C ₇ alkynyl, or R ₄ and R ₅ can jointly form a spiro C ₃ to C ₈ carbocycle.

R ₆ is C ₁ to C ₁₂ linear or branched alkyl, C ₂ to C ₇ linear or branched alkenyl or alkynyl, C ₅ to C ₁₃ aryl, with C ₆ to C ₂₁ aralkyl groups of 5 to 13 carbon atoms; 5 to 13 membered heteroaryl groups, 6 to 21 membered heteroaralkyl groups having 5 to 13 atoms in the heteroaryl part, C ₄ to C ₈ cycloalkyl, C ₅ to C ₁₆ cycloalkylalkyl having 4 to 8 carbon atoms on the cycloalkyl ring;

R ₇ and R ₈ are independently selected from hydrogen, C ₁ to C ₁₂ straight or branched chain alkyl, C ₂ to C ₇ straight or branched alkenyl or alkynyl, C ₅ to C ₁₃ Aryl, a _C6 to _C21 aralkyl group having 5 to 13 carbon atoms in the aryl part, a 5- to 13-membered heteroaryl group, a 6- to 6-membered heteroaryl group having 5 to 13 atoms in the heteroaryl part A 21-membered heteroarylalkyl group, or _R7 and _R8 may together form a cycloalkyl or heterocyclic ring having 4 to 8 carbon atoms in the ring and optionally one to two atoms selected from nitrogen, oxygen or sulfur alkyl;

wherein any of the R _to R groups having an aryl, heteroaryl, cycloalkyl or _{heterocycloalkyl} moiety may optionally be present in the aryl, heteroaryl, cycloalkyl or heterocycloalkyl moiety Substituted by 1 to about 5 substituents independently selected from halogen, cyano, nitro or hydroxyl, _C1 to _C6 alkyl, or _C1 to _C6 alkoxy;

wherein said composition has a bulk density of at least about 0.5 g/cm ³ , preferably at least about 0.8 g/cm ³ .

[0051] In another embodiment, the present invention relates to solid immediate release pharmaceutical compositions comprising:

At least one compound of formula (I) or a pharmaceutically acceptable salt thereof:

in:

_R1 is hydrogen;

A is -(CH ₂ ) _n -, where n is 2; and

R _{and R} are hydrogen; and

wherein said composition has a bulk density of at least about 0.5 g/cm ³ , preferably at least about 0.8 g/cm ³ .

[0052] In other embodiments, the invention is directed to a single dosage form. In other embodiments, the invention relates to multiple dosage forms.

[0053] In a further embodiment, the invention relates to capsules. In a further embodiment, the present invention also relates to tablets.

[0054] In certain embodiments, the present invention relates to solid immediate release pharmaceutical compositions,

wherein the composition exhibits a plasma _Cmax of the compound of formula (I) when administered to a subject in need thereof of from about 80 ng/mL to about 4200 ng/mL, preferably at least about 200 ng/mL, more preferably at least about 270 ng /mL, even more preferably at least about 2940 ng/mL.

[0055] In certain embodiments, the present invention relates to solid immediate release pharmaceutical compositions,

wherein the composition exhibits a plasma _Tmax of the compound of formula (I) when administered to a subject in need thereof of from about 0.5 hours to about 4.0 hours.

[0056] In certain embodiments, the present invention relates to solid immediate release pharmaceutical compositions,

wherein the composition exhibits an AUC (t=0 to 12 hours) of the compound of formula (I) when administered to a subject in need thereof of from about 250 ng·h/mL to about 6,000 ng·h/mL, preferably At least about 510 ng·h/mL, more preferably at least about 1215 ng·h/mL, even more preferably at least about 1280 ng·h/mL, and still even more preferably at least about 2850 ng·h/mL. In a preferred embodiment, when the composition is administered at regular intervals (eg, every 12 hours) for one or more days, the AUC total daily exposure (t=0 to 24 hours) is from about 500 ng·h/mL to About 12,000 ng·h/mL, preferably at least about 1020 ng·h/mL, more preferably at least about 2430 ng·h/mL, even more preferably 2560 ng·h/mL, and still even more preferably at least about 5700 ng·h/mL.

[0057] The solid pharmaceutical dosage form of the present invention may be any solid dosage form suitable for oral administration. Examples of suitable solid dosage forms include powders, capsules, tablets, pills, lozenges, cachets and pellets. Preferably, solid dosage forms suitable for oral administration are capsules or tablets. These dosage forms can be enteric coated or prepared for immediate release. In a preferred embodiment, the capsules or tablets are enteric coated.

[0058] As understood by those skilled in the art, the capsule material may be a hard capsule material or a soft capsule material, and generally includes an odorless, easy-to-administer and water-soluble compound such as gelatin, starch or fibrous material. Capsules are preferably sealed, for example with gelatin bands or the like. See, eg, Remiragtorn: The Science and Practice of Plzarmacy, 20th Ed. (Easton, PA: Mack Publishing Company, 2000), which describes materials and methods for the preparation of encapsulated pharmaceuticals.

[0059] Although not required, the enteric coating is typically a polymeric material. Preferred enteric coating materials include bioerodible, gradually hydrolyzed and/or water-soluble polymers. "Coating weight", or the relative amount of coating material per capsule, generally controls the time interval between ingestion and drug release. Any coating should be applied to a sufficient thickness so that the entire coating is insoluble in gastrointestinal fluids at a pH below about 5, but soluble in gastrointestinal fluids at a pH of about 5 and above. It is contemplated that any anionic polymer exhibiting a pH-dependent dissolution profile in the practice of the present invention may be used as an enteric coating to achieve delivery of the active agent to the lower gastrointestinal tract. The choice of specific enteric coating material depends on the following properties: resistance to dissolution and disintegration in the stomach; impermeability to gastric fluids and drug/carrier/enzyme while in the stomach; dissolution or rapid disintegration at the target intestinal site physical and chemical stability during storage; non-toxicity; ease of application as a coating (matrix affinity);

Suitable enteric coating material includes but not limited to: cellulose polymer, such as hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose, methyl cellulose, ethyl cellulose, Cellulose acetate, Cellulose acetate phthalate, Cellulose acetate-1,2,4-trimesate, Hydroxypropyl methylcellulose phthalate, Hydroxypropyl methylcellulose succinate (hydroxypropylme-thyl cellulose succinate) and sodium carboxymethylcellulose; propylene polymers and copolymers, preferably composed of acrylic acid, methacrylic acid, methyl acrylate, ammonium methyl acrylate, ethyl acrylate, methyl methacrylate and/or or ethyl methacrylate polymers and copolymers (such as those sold under the trade name EUDRAGIT); ethylene polymers and copolymers such as crospovidone (PVP), polyvinyl acetate, poly Vinyl acetate phthalate, vinyl acetate crotonic acid copolymer, and ethylene-vinyl acetate copolymer; and shellac (refined shellac). Combinations of different coating materials can also be used to coat individual capsules.

[0061] Enteric coatings provide controlled release of the active substance such that drug release can be accomplished at some generally predictable site in the lower gastrointestinal tract, below which point drug release would occur without an enteric coating. Enteric coatings also prevent exposure of hydrophilic therapeutic agents and carriers to the epithelial and mucosal tissues of the oral cavity, pharynx, esophagus, and stomach, as well as the enzymes associated with these tissues. The enteric coating thus helps to protect the active agent and the patient's gut from any adverse events before the drug is released at the site where it needs to be delivered. Furthermore, the coated capsules of the present invention optimize drug absorption, active agent protection and safety. Multiple layers of enteric coatings aimed at releasing the active agent in different parts of the lower GI tract will be more effective and consistently improve delivery throughout the lower GI tract.

[0062] The coating can, and preferably includes, a plasticizer to prevent the formation of voids and fissures that would allow gastric juices to penetrate. Suitable plasticizers include, but are not limited to, triethyl citrate (GITROFLEX 2), triacetin (triacetin), acetyl triethyl citrate (CITROFLEC A2), CARBOWAX 400 (polyethylene glycol 400), diethyl phthalate, tributyl citrate, acetyl monoglyceride, glycerin, fatty acid esters, propylene glycol and dibutyl phthalate. In particular, coatings comprising anionic carboxyacrylic polymers generally comprise less than about 50%, preferably less than about 30%, and more preferably from about 10% to about 25% by weight of the total weight of the coating. Plasticizers, especially dibutyl phthalate, polyethylene glycol, triethyl citrate and glyceryl triacetate. The coating may also contain other coating excipients such as anti-tacking agents, antifoaming agents, lubricants (e.g., magnesium stearate) and stabilizers (e.g., hyprolose, acids and bases) to dissolve or Disperses coating materials and improves coating properties and coated products.

[0063] In a preferred embodiment, the enteric-coated capsule or the enteric-coated tablet comprises a coating formed from an anionic polymer selected from the group consisting of methacrylic acid copolymers, acetic acid phthalates Cellulose, hydroxypropylmethylcellulose phthalate, polyvinyl acetate phthalate, shellac, hydroxypropylmethylcellulose acetate succinate -

-te) and carboxymethylcellulose. In a particularly preferred embodiment, the enteric coating is a methacrylic acid copolymer.

[0064] The coating can be applied to the capsule or tablet using conventional coating methods and equipment. For example, enteric coatings can be applied to capsules using coating pans, airless spray techniques, fluid bed coating equipment or the like. Detailed information on materials, equipment and methods for preparing coated dosage forms can be found in Pharmaceutical Dosage Forms: Tablets, eds. Liebermanden et al. (New York: Marcel Dekker, 1989), and Ansel et al., Pharnzaceutical Dosage Forms and Drug Delivery Systems , 6th Edition (Media, PA: Williams Wilkins, 1995). As noted above, the thickness of the coating must be sufficient to ensure that the oral dosage form remains intact until it reaches the lower intestinal tract where local release is desired.

[0065] In another embodiment of the invention, the solid pharmaceutical dosage form is a unit dose form or a multi-dose form. In such form, the composition can be subdivided into single or multiple doses containing appropriate quantities of the active ingredient. The dosage form can be a packaged composition. Accordingly, the present invention also provides an effective unit dose or multiple doses comprising at least one compound of formula (I) or a pharmaceutically acceptable salt thereof suitable for oral administration; at least one pharmaceutically acceptable absorption enhancer; and Solid pharmaceutical dosage form in unit dose form or in multi-dose form optionally with at least one additive for forming a solid dosage form.

[0066] Those skilled in the art will recognize that the preferred effective unit dose or multiple doses will depend, for example, on the condition to be treated and the particular compound of formula I selected. For example, it is believed that compounds of formula (I) in which R _{and /} or R are moieties B, C or _D have improved bioavailability relative to compounds of formula (I) in which R _and R are hydrogen and thus may Administer at low doses. However, preferably, the dose (whether in unit dose or in multiple doses) of the compound of formula (I) which is beneficial in the present invention is administered orally in the range of about 400 mg (200 mg BID) to about 4000 mg (2000 mg BID) per day, more preferably In the range of about 400 mg (200 mg BID) to about 3200 mg (1600 mg BID). In certain embodiments, the dose (whether unit dose or multiple doses) of a compound of formula (I) beneficial in the present invention administered orally per day will range from about 800 mg (400 mg BID) to about 3200 mg (1600 mg BID) More preferably in the range of about 800 mg (400 mg BID) to about 1200 mg (600 mg BID).

In above-mentioned formula (I):

R ₁ is hydrogen, C ₁ to C ₆ alkyl, C ₂ to C ₇ acyl, C ₁ to C ₆ alkanesulfonyl, or C ₆ to C ₁₄ aroyl;

A is an alkylene group of 1 to 4 carbon atoms or an alkenylene group of 2 to 4 carbon atoms;

R ₂ and R ₃ are independently selected from hydrogen,

R ₄ and R ₅ are independently selected from hydrogen, C ₁ to C ₄ alkyl, C ₅ to C ₇ aryl, C ₆ to C ₁₅ aralkyl having 5 to 7 carbon atoms in the aromatic ring , C ₂ to C ₇ alkenyl, or C ₂ to C ₇ alkynyl, or R ₄ and R ₅ can jointly form a spiro C ₃ to C ₈ carbocycle;

R ₆ is C ₁ to C ₁₂ linear or branched alkyl, C ₂ to C ₇ linear or branched alkenyl or alkynyl, C ₅ to C ₁₃ aryl, with C ₆ to C ₂₁ aralkyl groups of 5 to 13 carbon atoms; 5 to 13 membered heteroaryl groups, 6 to 21 membered heteroaralkyl groups having 5 to 13 atoms in the heteroaryl part, C ₄ to C ₈ cycloalkyl, C ₅ to C ₁₆ cycloalkylalkyl having 4 to 8 carbon atoms on the cycloalkyl ring;

R ₇ and R ₈ are independently selected from hydrogen, C ₁ to C ₁₂ straight or branched chain alkyl, C ₂ to C ₇ straight or branched alkenyl or alkynyl, C ₅ to C ₁₃ Aryl, _C6 to _{C2 aralkyl} having 5 to 13 carbon atoms in the aryl portion, 5 to 13 membered heteroaryl, 6 membered having 5 to 13 atoms in the heteroaryl portion to a 21-membered heteroarylalkyl group, or _R and _R may together form a cycloalkyl group having 4 to 8 carbon atoms in the ring and optionally one to two atoms selected from nitrogen, oxygen or sulfur, or Heterocycloalkyl;

wherein any of the R _to R groups having an aryl, heteroaryl, cycloalkyl or _{heterocycloalkyl} moiety may optionally be present in the aryl, heteroaryl, cycloalkyl or heterocycloalkyl moiety Substituted by 1 to about 5 substituents independently selected from halogen, cyano, nitro or hydroxy, C ₁ to C ₆ alkyl, or C ₁ to C ₆ alkoxy.

[0068] In one embodiment of the present invention, formula (I) R ₁ is preferably hydrogen or C ₁ to C ₄ alkyl and more preferably H.

[0069] In another embodiment of the present invention, A of formula (I) is preferably an alkylene group, -(CH ₂ ) _n -, wherein n is 1 to 3, more preferably 1 to 2 and most preferably 2 .

In another embodiment, when it is necessary to form [2-(8,9-dioxo-2,6-diazabicyclo[5.2.0]non-1(7)-en-2-yl ) alkyl] phosphoric acid derivatives, preferably at least one of R ₂ and R ₃ is not H.

In other embodiments, R _and R of formula (I) are H or (B) or (D) _moiety , more preferably H or (B) moiety, most preferably both are ( Part B) wherein R ₄ , R ₅ and R ₆ are as defined above. When neither _R2 nor _R3 are hydrogen, they are preferably the same group.

[0072] In another preferred embodiment of the present invention, R ₂ and R ₃ are both preferably hydrogen.

[0073] For (B), (C), and (D) moieties, R ₄ and R ₅ are preferably H or C ₁ to C ₄ alkyl, more preferably H or methyl. R ₆ is preferably a C ₃ to C ₁₀ linear or branched alkyl group, a C ₅ to C ₇ aryl group, a 5- to 7-membered heteroaryl group, or a group having 5 to 7 carbon atoms in the ring Cycloalkyl. In a preferred embodiment, R ₆ is a C ₅ to C ₇ aryl group.

[0074] In another more preferred embodiment of the present invention, R ₁ is H or C ₁ to C ₄ alkyl; A is an alkylene group having the formula -(CH ₂ ) _n -, wherein n is 1 to 3; R ₂ and R ₃ are independently H or:

R ₄ and R ₅ are independently H or C ₁ to C ₄ alkyl; and R ₆ is C ₃ to C ₁₀ linear or branched alkyl, C ₅ to C ₇ aryl, 5-membered to 7-membered heteroaryl, cycloalkyl having 5 to 7 carbon atoms in the ring.

Specific examples of compounds useful in the present invention include the following compounds:

[2-(8,9-dioxo-2,6-diazabicyclo[5.2.0]non-1(7)-en-2-yl)ethyl]phosphoric acid;

3-{2-[8,9-dioxo-2,6-diazabicyclo[5.2.0]non-1(7)-en-2-yl]ethyl}-3-epoxy-7 -Oxo-7-phenyl-2,4,6-trioxa-3-phospha-hept-1-ylbenzoate;

3-{2-[8,9-dioxo-2,6-diazabicyclo[5.2.0]non-1(7)-en-2-yl]ethyl}-3-epoxy-7 - Oxo-8-propyl-2,4,6-trioxa-3-phosphaundec-1-yl 2-propylpentanoate;

2,2-Dimethyl-propionic acid (2,2-dimethyl-propionyloxymethoxy (propionyloxymet-hoxy))-[2-(8,9-dioxo-2,6-di Aza-bicyclo[5.2.0]non-1(7)-en-2-yl)-ethyl]-phosphinoyloxymethyl (phosphinoyloxymethyl) ester;

7-cyclohexyl-3-{2-[8,9-dioxo-2,6-diazabicyclo[5.2.0]non-1(7)-en-2-yl]ethyl}-1 , 5-Dimethyl-3-epoxy-7-oxo-2,4,6-trioxa-3-phosphahepta-1-ylcyclohexanecarboxylate (cyclohexanecarboxylate);

7-cyclohexyl-3-{2-[8,9-dioxo-2,6-diazabicyclo[5.2.0]non-1(7)-en-2-yl]ethyl}-3 - Epoxy-7-oxo-2,4,6-trioxa-3-phosphahepta-1-ylcyclohexanecarboxylate;

[2-(8,9-Dioxo-2,6-diaza-bicyclo[5.2.0]non-1-(7)-en-2-yl)-ethyl]-diisopropoxyphosphate Diisopropoxycarbonyloxymethyl (diisopropoxycarbonyloxymethyl) ester;

[2-[8,9-dioxo-2,6-diazabicyclo[5.2.0]non-1(7)-en-2-yl]ethyl]-phosphobis[1-(benzoyl Oxy)ethyl] ester;

Benzoic acid [2-(8,9-dioxo-2,6-diaza-bicyclo[5.2.0]non-1(7)-en-2-yl)-ethyl]-hydroxy-phosphine oxide methyl esters; and

[2-(8,9-Dioxo-2,6-diaza-bicyclo[5.2.0]non-1(7)-en-2-yl)-ethyl]-phosphate dimethylform Amylmethoxy (didimethyl carbamoyloxymethyl) ester;

or a pharmaceutically acceptable salt thereof.

[0076] Compounds of interest in the present invention may contain asymmetric carbon atoms and/or phosphorus atoms, thus giving rise to optical isomers and diastereomers. Although no consideration of stereochemistry is shown in formula (I), the present invention includes such optical isomers and diastereomers; racemates and resolved, enantiomerically pure R and S stereo Isomers; other mixtures of R and S stereoisomers and pharmaceutically acceptable salts thereof.

[0077] Where one enantiomer is preferred, it may in certain embodiments be substantially free of the corresponding enantiomer. Thus, an enantiomer substantially free of the corresponding enantiomer refers to a compound which is isolated or isolated by separation techniques or which is prepared free of the corresponding enantiomer. As used herein, "substantially free" refers to a mixture of different forms of enantiomers consisting of a major proportion of one enantiomer. In a preferred embodiment, the mixture contains at least about 90% by weight of the preferred enantiomer. In other embodiments of the invention, the mixture comprises at least about 99% by weight of the preferred enantiomer. Preferred enantiomers may be isolated from racemic mixtures by any method known to those skilled in the art including high performance liquid chromatography (HPLC) and formation and crystallization of chiral salts or prepared by the methods described herein . See, for example, Jacques, et al., Enayitiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen, S.H., et al., Tetrahedron, 33:2725 (1977); Eliel, E.L. Stereochemistry of Carbon Cornpounds, (McGraw- Hill, NY, 1962); Wilen, S.H. Tables of Resolving Agents and Optical Resolutions, p.268 (E.L. Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN 1972).

[0078] Those skilled in the art will also recognize that tautomers of formula (I) may exist. The present invention includes the use of all such tautomers not shown in formula (I).

[0079] Compounds of interest in the present invention also include pharmaceutically acceptable salts of compounds of formula (I). By "pharmaceutically acceptable salt" salt it is meant any compound formed by the addition of a pharmaceutically acceptable base and a compound of formula (I) which forms the corresponding salt. By the term "pharmaceutically acceptable" it is meant a substance which is suitable from a toxicological point of view for use in pharmaceutical applications and which does not adversely interact with the active ingredient. Preferably, the pharmaceutically acceptable salt is an alkali metal (sodium, potassium, lithium) or alkaline earth metal (calcium, magnesium) salt of a compound of formula (I), or a pharmaceutically acceptable salt obtained from ammonia or a basic amine. The salt of the compound of formula (I) of the cation. Examples of the latter include, but are not limited to, ammonium, monomethylammonium, dimethylammonium or trimethylammonium, monoethylammonium, diethylammonium or triethylammonium, monopropylammonium, dipropylammonium or tripropylammonium (iso and normal), Ethyldimethylammonium, benzyldimethylammonium, cyclohexylammonium, benzylammonium, benzhydrylammonium, pyridinium, morpholinium, pyrrolidinium, piperazine, 1-picoline , 1-isopropylpyrrolidinium, 1,4-dimethylpiperazine, 1-n-butylpyridinium, 2-methylpyridinium, 1-ethyl-2-methylpyridinium, mono ethanolammonium, diethanolammonium, or triethanolammonium, tris(hydroxymethyl)methylammonium, or phenylmonoethanolammonium. Preferably, a salt can be formed when one of _R2 or _R3 is hydrogen.

Beneficial compound in the present invention can be prepared by the compound of synthetic formula (II) according to US-A-5,168,103, US-A-5,240,946, US-A-5,990,307 and US-A-6,011,168 described method, wherein A and R ₁ are defined as formula (I):

The entire contents of which are incorporated herein by reference. A preferred synthetic route is described in Example 5 of US-A-5,990,307 and US-A-6,011,168.

[0081] In order to form a compound in which at least one of _R2 or _R3 in formula (I) is other than hydrogen, the compound of formula (II) obtained is then dissolved in a suitable solvent, such as dimethylformamide. As used herein, "suitable solvent" means that the compound of formula (II) can be dissolved therein and does not react therewith. Preferably, an acid scavenger (reacted with a by-product of the acid halide reaction), such as an amine, is added to the reaction mixture, preferably at room temperature. Preferably, the amine is a sterically hindered secondary or tertiary amine, more preferably a tertiary amine such as diisopropylethylamine. An appropriately substituted haloester of the formula is added to the reaction mixture,

wherein R ₄ , R ₅ and R ₆ are as defined in formula (I), and Y is a halogen atom. The reaction mixture is heated from about 50°C to about 80°C, more preferably from about 65°C to about 75°C, for a sufficient reaction time to react the haloester with the compound of formula (II) to form the compound of formula (I). Usually, in order to obtain a better yield, the reaction time is about 20 hours to about 40 hours, more preferably about 25 hours to about 35 hours. After completion of the reaction, the reaction mixture is preferably cooled to room temperature and the compound of formula (I) is isolated using conventional techniques known to those skilled in the art. A preferred method of isolation is to partition the reaction mixture between a mild base such as aqueous sodium bicarbonate and an organic solvent such as ethyl acetate. The extraction of the aqueous phase is preferably repeated several times with an organic solvent and the combined organic layers are washed again with a weak base. The organic layer is then dried, eg with brine and over magnesium sulfate, filtered and evaporated. The residue is then subjected to flash chromatography on silica gel to isolate the compounds, preferably using conventional techniques.

[0082] The compound of formula (I) is present in a solid pharmaceutical dosage form in an effective amount suitable for oral administration. As used herein, an "effective amount" is at least the minimum amount of a compound of formula (I), or a pharmaceutically acceptable salt formed therefrom, that treats the condition in question in a mammal. The effective amount will depend on such variables as the particular composition employed, the severity of the symptoms and the particular patient being treated. To determine an effective amount of a compound to administer, a physician can estimate the effect of a particular compound of formula (I), for example, by gradually increasing the dose until the desired level of symptomatic relief is achieved. The continued dosing regimen can then be adjusted to achieve the desired results. For oral administration, the compound of the invention is preferably gradually increased in the patient in amounts from 1 mg/kg to 10 mg/kg until the desired level of symptom relief is achieved. The continued dosing regimen can then be adjusted to achieve the desired results, with oral dosages preferably in the range of about 200 mg/day to about 4000 mg/day, more preferably about 400 mg/day to about 3200 mg/day, even more preferably at least about 800 mg /day, even more preferably at least about 1600 mg/day, even more preferably at least about 3200 mg/day. Compounds of the invention may be administered in a single oral dose (e.g., one 600 mg tablet or capsule) or in multiple oral doses (e.g., three 200 mg tablets or capsules; two 300 mg tablets or capsules) Patient administration, preferably in the form of tablets or capsules to the patient.

In a preferred embodiment, the compound of formula (I) is present in a solid pharmaceutical dosage form at a level of from about 25% by weight to about 99.5% by weight of the total weight of the pharmaceutical composition, more preferably as It is present at a level of about 50% to about 99.5% by weight based on the total weight of the pharmaceutical composition, even more preferably at a level of about 60% to about 99.5% by weight based on the total weight of the solid pharmaceutical dosage form. Even more preferably present at a level of from about 67% to about 99.5% by weight, based on the total weight of the solid pharmaceutical dosage form.

[0084] In addition to comprising an effective amount of at least one compound of formula (I), the solid pharmaceutical dosage form of the present invention preferably comprises at least one pharmaceutically acceptable absorption enhancer selected from the group consisting of surfactants, bile salts, fatty acids , fatty acid salts, complexing agents, acylcarnitines, acylcholines or mixtures thereof. In a preferred embodiment, the absorption enhancer is present in the solid pharmaceutical dosage form in an amount of from about 0.25% to about 50% by weight, based on the total weight of the solid pharmaceutical dosage form.

[0085] Suitable surfactants include, for example, ionic surfactants, nonionic surfactants, or mixtures thereof. Typical ionic surfactants include sodium lauryl sulfate, sodium dioctyl sulfonate succinate or mixtures thereof. Typical nonionic surfactants include polyoxyethylene alkyl ethers, polyoxyethylene alkyl esters, polysorbates or mixtures thereof.

[0086] Suitable polyoxyethylene alkyl esters include, for example, polyethylene glycol-20 sorbitan monooleate sold under the tradename TWEEN 80.

[0087] Suitable bile salts include, for example, sodium cholate, sodium deoxycholate, or mixtures thereof.

[0088] Suitable fatty acids include, for example, oleic acid. Suitable fatty acid salts include, for example, sodium caprate.

[0089] Suitable complexing agents include, for example, ethylenediaminetetraacetic acid (EDTA) and its salts, including its sodium salt.

[0090] Suitable acylcarnitines include, for example, palmitoylcarnitine. Suitable acylcholines include, for example, lauroylcholine.

[0091] The solid pharmaceutical dosage form of the present invention may optionally comprise at least one additive for forming the solid dosage form of the pharmaceutical composition. Suitable optional additives include fillers, disintegrants, binders, lubricants or mixtures thereof. Absorption enhancers may also be used as the only additive or as one of the additives used to form the solid dosage form.

[0092] Typical fillers include, for example, lactose, microcrystalline cellulose, mannitol, calcium phosphate, pregelatinized starch, pregelatinized sucrose, or mixtures thereof. Microcrystalline cellulose is preferred, especially as an intragranular and extragranular component.

[0093] Typical disintegrants include, for example, croscarmellose sodium, starch, sodium starch glycolate, pregelatinized starch, crospovidone, and mixtures thereof. Croscarmellose sodium is preferred, especially as an intragranular and extragranular component.

[0094] Typical binders include, for example, povidone (also known as polyvinylpyrrolidone or PVP), hydroxypropylmethylcellulose, polyvinyl alcohol, gelatin, gums, and mixtures thereof. Povidone is preferred. Preferably, if a binder is present, it is included in the composition in an amount of preferably from about 0.5% by weight to about 10% by weight, more preferably at least about 1.5% by weight, most preferably at least about 2.5% by weight , based on the total weight of the composition.

[0095] Typical lubricants include, for example, magnesium stearate, sodium stearyl fumarate, and mixtures thereof.

[0096] Preferably, the additives used to form the solid dosage form total at least about 0.25% by weight, more preferably from about 0.25% by weight to about 95% by weight, most preferably from about 0.25% by weight to about 95% by weight, based on the total weight of the composition. 33% by weight.

[0097] Solid pharmaceutical dosage forms can be prepared by conventional manufacturing techniques for forming oral solid dosage forms, including but not limited to wet processing, dry processing, fluid bed granulation and direct compression techniques. Such techniques are described in Remington: The Science and Practice of Pharmacy, 20th Ed. (Easton, PA: Mack Publishing Company, 2000), pages 858-893, the disclosure of which is incorporated herein by reference in its entirety. The density of the powder mixture was increased from 0.33 g/ml to 0.59 g/ml using wet granulation technology in Examples 1 and 2, making it possible to encapsulate 300 mg of active ingredient in #0 size HPMC capsules ([2-(8,9 -dioxo-2,6-diazabicyclo[5.2.0]non-1(7)-en-2-yl)ethyl]phosphoric acid).

[0098] The solid pharmaceutical dosage forms of the present invention may also optionally contain one or more antimicrobial preservatives to prevent the growth of microorganisms during storage and multi-dose use. Examples of suitable preservatives are benzalkonium chloride, thimersal, chlorobutanol or parabens or combinations thereof. Although the concentration of preservative in the composition depends on the preservative used, the total amount of preservative in the composition is preferably in the range of about 0.1% to about 2.0% by weight, based on the total weight of the composition.

[0099] In another embodiment of the invention, the solid pharmaceutical dosage form may contain one or more other pharmaceutically active agents such as those used to treat any other medical condition present in mammals. Examples of such pharmaceutically active agents include pain-relieving, anti-angiogenic, anti-neoplastic, anti-diabetic, anti-infective or gastrointestinal drugs, or combinations thereof. A more complete listing of pharmaceutically active agents can be found in Physicians' Desk Reference, 55th Edition, 2001, published by Medical Economics Co., Inc., Montvale. Each of these drugs can be administered according to therapeutically effective dosages and dosing regimens known in the art, such as those described in Physicians' Desk Reference, 55th Edition, 2001, published by Medical Economics Co., Inc., Montvale.

[0100] The invention also includes kits or packages of pharmaceutical formulations designed for use in the dosing regimens and methods described herein. These kits are preferably designed for oral administration per day for a specified period or period, preferably for oral administration of a prescribed amount per day, and are combined so as to indicate a single oral formulation or oral formulation to be taken each day in a dosing regimen or cycle. Jointly designed. Preferably, each kit includes oral tablets for daily administration, in some embodiments a single oral tablet contains the stated combined daily doses, in other embodiments the individual compounds are administered as separate formulations or compositions. application. Most preferably the pack or kit will have a schedule or schedule for each day of the week involving administration of the appropriate composition on the appropriate day or time.

[0101] In another embodiment of the invention, the invention provides a method of treating one or more disorders associated with glutamate abnormalities comprising orally administering to a mammal in need thereof a therapeutically effective amount of at least one Compounds of formula (I). As used herein, "associated with" refers to a condition caused directly or indirectly by glutamate abnormalities. "Glutamate abnormality"refers to any condition resulting from a disease or disorder involving glutamate and/or its receptors as a contributing factor to the disease or disorder. Conditions believed to be associated with glutamate abnormalities include, but are not limited to, vascular diseases associated with glutamate abnormalities, such as cerebrovascular diseases including, but not limited to, those leading to a range of conditions such as, for example, thromboembolic or hemorrhagic stroke Cerebral ischemia (eg, stroke) or infarction, or cerebral vasospasm; traumatic brain injury; muscle spasms; convulsive disorders such as epilepsy or status epilepticus; glaucoma; pain; anxiety disorders such as panic attacks, agoraphobia, panic attacks Sexual disorder, specific phobia, social phobia, obsessive-compulsive disorder, post-traumatic stress disorder, acute stress disorder, general anxiety disorder, separation anxiety disorder, or substance-induced anxiety disorder; mood disorders such as bipolar disorder (eg, , bipolar I disorder, bipolar II disorder, and cycloaffective disorder), depression (eg, major depressive disorder, dysthymia, or substance-induced mood disorder), mood episodes (eg, major depressive episode, manic episodes, mixed episodes, and hypomanic episodes); schizophrenia; schizophreniform disorders; schizoaffective disorders; cognitive impairments such as memory loss; and chronic neurodegenerative disorders such as Parkinson's disease, Huntington's disease, Alzheimer's disease, amyotrophic lateral sclerosis, or a chronic dementia-related disorder such as Lewy body disease, Alzheimer's disease, fronto temporal dementia, or AIDS . For the mental disorders listed above such as schizophrenia, mood disorders and anxiety disorders, refer to Diagnostic and Statistical Manual of mental disorders, 4th edition, Washington, DC, American Psychiatric Association (1994) for a more complete list of various mental disorders description of. Other conditions thought to be associated with glutamate abnormalities include inflammatory diseases; hypoglycemia; end-organ complications of diabetes; anoxia; and spinal cord injury. The compounds of the invention are also useful in the treatment of fibromyalgia, irritable bowel syndrome, and the prevention of complications of herpes zoster (shingles) such as postherpetic neuralgia. The pharmaceutical composition of the present invention can also be used to prevent resistance to opioid analgesics or to help control withdrawal symptoms of addictive drugs. Accordingly, the present invention provides methods for the treatment of the various disorders described above, comprising orally administering a therapeutically effective amount of at least one compound of general formula (I) to a mammal in need thereof.

[0102] In a preferred embodiment, the beneficial compounds of the present invention are used to treat pain. Pain can be, for example, acute pain (short duration) or chronic pain (recurring or persistent). Pain can also be central or peripheral.

Examples of pain which may be acute or chronic and which may be treated in accordance with the methods of the invention include inflammatory pain, musculoskeletal pain, bony pain, low back pain, neck or upper back pain, visceral pain, Somatic pain, neuropathic pain, cancer pain, pain resulting from injury or surgery such as burns or toothache, or headache such as migraine or tension headache, or a combination of these pains. Those skilled in the art will recognize that these pains can overlap. For example, pain caused by inflammation may also be visceral or musculoskeletal in nature.

In a preferred embodiment of the present invention, the beneficial compounds of the present invention are administered to mammals to treat chronic pain, such as neuropathic pain associated with peripheral or central nervous system damage or disease; cancer pain; visceral pain visceral pain, eg, associated with the abdomen, pelvic and/or perineal region, or pancreatitis; musculoskeletal pain, eg, associated with the lower or upper back, spine, fibromylagia, temporomandibular joint, or myofascial pain syndrome musculoskeletal pain; bony pain, such as that associated with bone or joint degenerative disease such as osteoarthritis, rheumatoid arthritis, or spinal stenosis; headache, such as migraine or tension headache; Or pain associated with infections such as HIV, sickle cell anemia, autoimmune disorders, multiple sclerosis, or inflammation such as osteoarthritis or rheumatoid arthritis.

In a more preferred embodiment, the compounds of interest of the present invention are used according to the methods described herein for the treatment of chronic pain which is neuropathic pain, visceral pain, musculoskeletal pain, bony pain, cancer pain or Inflammatory pain or a combination thereof. Inflammatory pain can be associated with a variety of medical conditions such as osteoarthritis, rheumatoid arthritis, surgery or injury. Neuropathic pain includes peripheral neuropathic pain, central neuropathic pain or a combination thereof. Neuropathic pain can be associated with, for example, diabetic neuropathy, postherpetic neuralgia, trigeminal neuralgia, complex regional pain syndrome, lumbar or cervical radiculopathy, fibromyalgia, glossopharyngeal neuralgia, sympathetic dystrophy, Causalgia, thalamic syndrome, nerve root avulsion, monoclonal gammopathy of undetermined significance (MGUS) neuropathy, sarcoid polyneuropathy, HIV due to various causes such as drugs used to treat HIV Associated neuropathy, peripheral neuropathy such as peripheral neuropathy in connective tissue disease, neoplastic sensory neuropathy, familial amyloid polyneuropathy, acquired amyloid polyneuropathy, hereditary neuropathy, neuropathy in renal failure, hereditary sensory Autonomic neuropathy, Fabry disease, celiac disease, or nerve damage resulting from peripheral and/or central sensitization from injury, such as phantom limb pain, sympathetic dystrophy, or postthoracotomy pain, Cancer including neuropathy caused by chemotherapy or other agents used to treat the disease, chemical damage, toxins such as arsenic neuropathy, nutritional deficiencies, or viral or bacterial infections such as those associated with shingles or HIV disease, or a combination thereof. The methods of use of the compounds of the present invention further include the treatment of conditions wherein neuropathic pain is secondary to metastatic infiltration, dynamism, burns, or central pain associated with thalamic disorders.

[0106] Neuropathic pain as described above may also in some cases be classified as "painful thin fiber neuropathy", such as primary thin fiber painful sensory neuropathy, or "painful large fiber neuropathy" such as demyelination Demylinating neuropathy or axonal neuropathy or a combination thereof. For example, such neuropathies are more specifically described in J. Mendell et al., N. Engl. J. Med. 2003, 348: 1243-1255, which is hereby incorporated by reference in its entirety.

[0107] As previously stated, the methods of the present invention may be used in nature to treat somatic and/or visceral pain. For example, somatic pain that may be treated in accordance with the methods of the present invention includes pain associated with structural or soft tissue damage experienced during surgery, dental procedures, burns, or traumatic bodily injury. Examples of visceral pains that may be treated in accordance with the methods of the present invention include those associated with or resulting from diseases of the internal organs such as ulcerative colitis, irritable bowel syndrome, irritated bladder, clonal disease, rheumatism (joint pain), tumor, gastritis, pancreatitis, organ infection, or biliary tract disease, or a combination thereof. Those skilled in the art will also recognize that the pain treated in accordance with the methods of the present invention may also be associated with hyperalgesia, allodynia, or both. Furthermore, chronic pain can be present with or without peripheral or central sensitization.

[0108] Compounds of benefit in the present invention are also useful in the treatment of acute and/or chronic pain associated with a female condition, which may also be referred to as female-specific pain. Such pain includes pain experienced exclusively or predominantly by women, including those associated with menstruation, ovulation, pregnancy or childbirth, miscarriage, ectopic pregnancy, retrograde menstruation, rupture of follicular or corpus luteum cysts, irritation of pelvic viscera, uterine leiomyoma, uterine Endometriosis, endometriosis, infection and inflammation, ischemia of the pelvic organs, obstruction, intra-abdominal adhesions, anatomical malformations of the pelvic organs, ovarian abscess, loss of pelvic support, tumors, associated with pelvic congestion Pain or pain of non-gynecological origin.

[0109] As used herein, the terms "treating" or "treating" include, in addition to partially or completely alleviating pain that has occurred in a mammal, completely or partially inhibiting (eg, preventing) the occurrence of pain. Accordingly, the compound of the present invention can be administered to a mammal before the mammal experiences pain to partially or completely inhibit the onset of pain.

[0110] In one embodiment, compounds beneficial in the present invention may be administered prior to surgery or during a surgical procedure to partially or completely inhibit the occurrence of pain associated with the surgical procedure. In a preferred embodiment, the compounds of interest in the present invention are administered preferably from about 0.25 hours to about 4 hours prior to surgery. For surgical procedures of longer duration, the dosing is preferably repeated at each interval during the surgical procedure approximately commensurate with the in vivo half-life (T1 _/2 ) of the compound. In a preferred embodiment, administration of the formulation according to Example 1 is repeated approximately every 4 to 8 hours during the surgical procedure.

[0111] In another embodiment of the invention, it was discovered that administering a compound of interest in the present invention prior to a surgical procedure increases the potency and and/or effect, and/or reduce the amount of pain relief agent needed to treat postoperative pain. Accordingly, the present invention provides a method of treating pain associated with a surgical procedure comprising administering a beneficial compound of the invention before or during a surgical procedure, and administering a therapeutically effective amount of at least one pain-relieving compound after or during a surgical procedure. agents, such as opioid analgesics. In a preferred embodiment, the compound of the invention may also be administered to the mammal following a surgical procedure, preferably in combination with one or more pain relieving agents. As used herein, "surgical manipulation" includes all therapeutic, diagnostic, and/or cosmetic manipulations, dissection, mobilization, radiation, resection, chemical or physical alteration of any tissue, organ or body system, tissue, organ or body system Including but not limited to blood, blood vessels, fat, skin, connective tissue, muscle, internal organs, glands, bones, cartilage, nerves, bone marrow, fascia, meninges, sensory organs, brain or spinal cord. Surgical procedures include, for example, those performed on mammals using more recent surgical techniques such as lasers, ultrasound and radiation, as well as more conventional techniques.

[0112] In another embodiment, compounds of benefit in the present invention may be administered to completely or partially inhibit the onset of neuropathic pain conditions. For example, a compound of the invention may be administered to a mammal at risk of developing a neuropathic pain condition, eg, a mammal infected with herpes zoster or undergoing treatment for cancer.

[0113] In another embodiment of the present invention, a compound useful in the present invention may be administered to a mammal in combination with one or more other pharmaceutically active agents, for example for the treatment of any other medical condition present in the mammal. Those potions. Examples of such pharmaceutically active agents include pain relievers, antiangiogenic agents, antineoplastic agents, antidiabetic agents, antiinfective agents, or gastrointestinal agents, or combinations thereof.

[0114] A therapeutically effective amount of one or more other pharmaceutically active agents may be administered simultaneously with one or more compounds of the present invention (e.g., simultaneously administered alone or together in a pharmaceutical composition), and/or administered sequentially .

[0115] The method of administration of the other pharmaceutically active agents may be the same or different than the route of administration used for the compounds of the present invention. For example, other pharmaceutically active agents may be administered orally or parenterally, eg, intramuscularly, intraperitoneally, epidurally, intrathecally, intravenously, intramucosally, eg, intranasally or sublingually, subcutaneously or transdermally. The preferred route of administration depends on the particular pharmaceutically active agent chosen and its recommended route of administration known to those skilled in the art.

[0116] A more complete list of pharmaceutically active agents can be found in Physicians' Desk Reference, 55th Edition, 2001, published by Medical Economics Co., Inc., Montvale. Each of these drugs can be administered according to therapeutically effective amounts and regimens known in the art, such as those described in Physicians' Desk Reference, 55th Edition, 2001, published by Medical Economics Co., Inc., Montvale.

[0117] In a preferred embodiment of the invention, a beneficial compound of the invention may be administered to a mammal in combination with one or more other pain relieving agents to treat pain in the mammal. By "pain reliever" it is meant any drug that directly or indirectly treats the symptoms of pain. Examples of indirect pain relieving agents include, for example, anti-inflammatory drugs, such as antirheumatic drugs.

[0118] One or more other pain relieving agents may be administered concurrently with the compound of the invention (eg, concurrently alone or together in a pharmaceutical composition), and/or sequentially. Preferably, a compound of the invention and one or more pain relieving agents are administered in such a way that both are present in the mammal for a period of time to treat pain.

[0119] The other pain relieving agents may be administered by the same or a different route than that used for the compounds of the present invention. For example, the opioid is preferably administered by oral, intravenous, intranasal, or intramuscular routes of administration.

[0120] Those skilled in the art will recognize that the dosage of other pain relieving agents administered to a mammal will depend upon the particular pain relieving agent in question and the desired route of administration. Accordingly, other pain relieving agents may be dosed and administered according to practices known to those skilled in the art, for example as disclosed in references such as Physicians' Desk Reference, 55th Edition, 2001, published by Medical Economics Co., Inc., Montvale , those in NJ.

Examples of pain relieving agents that can be administered with the compounds of the present invention include analgesics such as non-narcotic analgesics or narcotic analgesics; anti-inflammatory drugs such as non-steroidal anti-inflammatory drugs (NSAIDs), steroids or Antirheumatics; migraine preparations such as beta-adrenergic blockers, ergot derivatives, or Isometheptene; tricyclic antidepressants such as amitryptyline, desipramine, or imipramine; antiepileptics such as gabapentin, Carbamazine, topiramate, valproate, or phenytoin; alpha ₂ agonists; or selective serotonin uptake inhibitors/selective norepinephrine uptake inhibitors, or combinations thereof. Those of skill in the art will recognize that some of the drugs described below act to reduce multiple conditions, such as pain and inflammation, while others may only reduce one symptom, such as pain. A specific example of a drug with multiple properties is aspirin, which is an anti-inflammatory drug when given in high doses, but is only an analgesic when given in low doses. Pain relieving agents may include any combination of the above drugs, for example, the pain relieving agent may be a combination of a non-narcotic analgesic and a narcotic analgesic.

[0122] In a preferred embodiment of the invention, at least one compound of the invention and at least one opioid analgesic are administered as previously described herein to treat pain. Compounds of the invention have been found to have beneficial effects such as reduced pain perception, increased time to pain relief, and/or compared to other comparable NMDA antagonists when administered with at least one opioid analgesic such as morphine. Minimize side effects.

[0123] The invention will now be illustrated with reference to the following specific, non-limiting examples. Those skilled in the art of organic synthesis will also know of other synthetic routes to the compounds of the invention. The reagents and intermediates used herein are either commercially available or can be prepared according to routine literature procedures.

[0124] In another embodiment, the present invention is directed to a method of forming a formulation comprising a compound of formula (I). The method comprises the steps of: forming wet granules; and forming a solid dosage form. Wet granules contain:

at least one binder, preferably povidone;

optionally at least one filler, preferably microcrystalline cellulose;

optionally at least one disintegrant, preferably croscarmellose sodium; and

At least one compound of formula (I) or a pharmaceutically acceptable salt thereof, preferably [2-(8,9-dioxo-2,6-diazabicyclo[5.2.0]nonan-1(7) -en-2-yl)ethyl]phosphoric acid or a pharmaceutically acceptable salt thereof.

[0125] In certain preferred embodiments, wet granules are formed by dry mixing at least one filler or disintegrant with the compound of formula (I) or a pharmaceutically acceptable salt thereof; A solution of at least one binder forming wet granules is formed by granulating the dry mixture.

In certain preferred embodiments, the method further comprises the steps of: drying the wet granules; milling the dry granules; then optionally mixing the above milled dry granules with one or more extragranular components, Preferably fillers and/or disintegrants are added to form wet granules.

[0127] In certain embodiments, the present invention relates to products prepared by the methods described above.

[0128] The invention will now be illustrated with reference to the following specific, non-limiting examples. Those skilled in the art of organic synthesis will also know of other synthetic routes to the compounds of the invention. The reagents and intermediates used herein are either commercially available or can be prepared according to routine literature procedures.

Example

[0129] The invention is further defined in the following examples, wherein all parts and percentages are by weight and temperatures are in degrees Celsius unless otherwise indicated. It should be understood that these Examples, while indicating preferred embodiments of the invention, are given by way of illustration only. From the above discussion and these examples, those skilled in the art can ascertain the essential characteristics of this invention, and those skilled in the art can make various changes and modifications to the present invention so as to adapt it to different usages and situations without departing from it. spirit and scope of the invention.

Example 1:

Capsule formulation (69.4% [2-(8,9-dioxo-2,6-diazabicyclo[5.2.0]non-1(7)-en-2-yl)ethyl]phosphoric acid)

[0130] Capsules of three strengths (100, 200, 300 mg capsules) were prepared from a common wet granulation. The batch size of the granules was 1297.8 g. The formula of [2-(8,9-dioxo-2,6-diazabicyclo[5.2.0]non-1(7)-en-2-yl)ethyl]phosphoric acid capsules is shown in the table 1.

Preparation of microcrystalline cellulose, [2-(8,9-dioxo-2,6-diazabicyclo[5.2.0]non-1(7)-en-2-yl)ethyl] Mixture of phosphoric acid and the intragranular fraction of croscarmellose sodium. A pure aqueous solution of povidone was prepared by dissolving povidone in purified water. The mixture was granulated with the povidone solution in a high shear granulator. When needed, additional purified water was added to achieve the desired granulation endpoint. The granules are then dried in a suitable drier, ground, and transferred to a mixer. The microcrystalline cellulose and croscarmellose sodium were added to the granules and mixed. Add magnesium stearate and mix. Assemble the capsule filling machine to fill #0 capsules. [2-(8,9-dioxo-2,6-diazabicyclo[5.2.0]non-1(7)-en-2-yl)ethyl]phosphoric acid (69.35% by weight, based on the total preparation by weight) with brown opaque hydroxypropyl methylcellulose (HPMC) #0 capsules using the target fill weight.

[0132] The analytical data for these capsules are shown in Table 2.

Table 1 components 100mg 200mg 300mg mg/capsule mg/capsule mg/capsule Intragranular [2-(8,9-dioxo-2,6-diazabicyclo[5.2.0]non-1(7)-en-2-yl)ethyl]phosphoric acid 100.00 200.00 300.00 Microcrystalline Cellulose (AVICEL PH101) 13.91 27.82 41.73 Povidone USP, 17PF 3.61 7.22 10.83 Croscarmellose Sodium 5.77 11.54 17.31 Extragranular Microcrystalline Cellulose (AVICEL PH101) 14.42 28.84 43.26 Croscarmellose Sodium 5.77 11.54 17.31 Magnesium stearate (vegetable grade) 0.72 1.44 2.16 total 144.20 288.40 432.60

Table 2 detection item result result result 100mg 200mg 300mg Concentration (HPLC) 98.3%LC 97.5%LC 98.9%LC Loading difference Average: 96.8% cv=3.8% Range: 89.9-101.2% Average: 98.0% cv = 2.7% Range: 94.5-101.8% Average: 99.7% cv = 2.7% Range: 94.5-101.8% Dissolution time average% scope% average% scope% average% scope% 15 marks 97.0 95-99 98.6 97-102 96.2 89-100 30 points 98.8 96-102 99.7 98-102 99.1 93-102 45 points 99.5 96-102 99.8 98-102 99.6 95-103

LC = labeled amount (label claim) RL = method reporting limit (Method reporting limit)

Example 2:

Capsule preparation (86.7% [2-(8,9-dioxo-2,6-diazabicyclo[5.2.0]non-1(7)-en-2yl)ethyl]phosphoric acid)

The preparation process of Example 1 is repeated using the following components: components 200mg mg/capsule Intragranular [2-(8,9-dioxo-2,6-diazabicyclo[5.2.0]non-1(7)-en-2-yl)ethyl]phosphoric acid 200.00 Povidone USP, 17PF 3.53 Croscarmellose Sodium 7.05 Microcrystalline Cellulose (AVICEL PH101) 14.1 Extragranular Croscarmellose Sodium 4.7 Magnesium stearate (vegetable grade) 1.18 total 230.56

Example 3:

Capsule preparation (69.35% [2-(8,9-dioxo-2,6-diazabicyclo[5.2.0]non-1(7)-en-2-yl)ethyl]phosphoric acid)

The preparation process of Example 1 is repeated using the following components: components 300mg mg/capsule Intragranular [2-(8,9-dioxo-2,6-diazabicyclo[5.2.0]non-1(7)-en-2-yl)ethyl]phosphoric acid 208.05 Povidone USP, 17PF 7.5 Croscarmellose Sodium 12.00 Microcrystalline Cellulose (AVICEL PH101) 28.95 Extragranular Microcrystalline Cellulose (AVICEL PH101) 30.00 Croscarmellose Sodium 12.00 Magnesium stearate (vegetable grade) 1.5 total 300

[0135] Co-granules containing 69.35% active ingredient were prepared by wet granulation. Capsules of 100 mg or 300 mg strength were prepared by filling #0 capsules with 144.20 mg and 432.6 mg of the final blend, respectively.

Example 4:

Enteric-coated tablet formulations

[0136] Tablet formulation studies were performed by wet granulation. 200 mg of [ ^2- (8,9- Dioxo-2,6-diazabicyclo[5.2.0]non-1(7)-en-2-yl)ethyl]phosphate tablet. The tablets are then coated with an enteric coating solution. This tablet is used as [2-(8,9-dioxo-2,6-diazabicyclo[5.2.0]non-1(7)-en-2-yl)ethyl]phosphoric acid 200 mg tablet The basic formulation of the agent.

component Feeding amount/tablet (mg) function Intragranular [2-(8,9-dioxo-2,6-diazabicyclo[5.2.0]non-1(7)-en-2-yl)ethyl]phosphate cross-linked carboxymethyl fiber Sodium povidone USP, 17PF extragranular microcrystalline cellulose (AVICEL PH101) croscarmellose sodium magnesium stearate 200.007.053.5314.104.701.18 Active ingredients Disintegrants Binders Diluents and Disintegrants Disintegrants Lubricants

[0137] Tablets remained intact in 0.01N HCL for 2 hours. The tablet disintegrated completely within 26 minutes in phosphate buffer (pH 6.8).

Example 5:

Tablet formulation comprising an enteric coating of sodium lauryl sulfate

A tablet formulation comprising an enteric coating of sodium lauryl sulfate was prepared according to the following table:

component Feeding amount/tablet (mg) function Intragranular [2-(8,9-dioxo-2,6-diazabicyclo[5.2.0]non-1(7)-en-2-yl)ethyl]phosphate cross-linked carboxymethyl fiber Sodium Povidone USP, 17PF Extragranular Microcrystalline Cellulose (AVICEL PH101) Croscarmellose Sodium Lauryl Sulfate Magnesium Stearate 200.007.053.5314.104.705.881.18 Active ingredients, disintegrants, binders, diluents and disintegrants, disintegrants, absorption enhancers, lubricants

[0139] The Visulution of the tablet was carried out in 0.01N HCL for 2 hours, and then carried out in phosphate buffer (pH 6.8) until the tablet disintegrated completely, and the vision time in the buffer was 24 minutes.

Embodiment 6:

Enteric-coated tablet formulation comprising tetrasodium EDTA

[0140] The enteric-coated tablet formulation comprising tetrasodium EDTA was prepared according to the table below:

component Feeding amount/tablet (mg) function Intragranular [2-(8,9-dioxo-2,6-diazabicyclo[5.2.0]non-1(7)-en-2-yl)ethyl]phosphate cross-linked carboxymethyl fiber Sodium povidone USP, 17PF extragranular microcrystalline cellulose (AVICEL PH101) croscarmellose sodium EDTA tetrasodium magnesium stearate 200.007.053.5314.104.707.051.18 Active ingredients, disintegrants, binders, diluents and disintegrants, disintegrants, absorption enhancers, lubricants

[0141] Carry out the Visulution of the tablet in 0.01N HCL for 2 hours, then carry out in phosphate buffer (pH 6.8) until the tablet disintegrates completely, the vision time in the buffer is 26 minutes.

Example 7: Enteric-Coated Tablet Formulation Comprising TWEEN80

A tablet formulation comprising an enteric coating of TWEEN80 was prepared according to the following table:

component Feeding amount/tablet (mg) function Intragranular [2-(8,9-dioxo-2,6-diazabicyclo[5.2.0]non-1(7)-en-2-yl)ethyl]phosphate microcrystalline cellulose (AVICEL PH101) Croscarmellose Sodium Polyethylene Glycol-20 Sorbitan Monooleate (TWEEN-80) Povidone USP, 17PF Extragranular Microcrystalline Cellulose (AVICEL PH101) Croscarmellose Sodium magnesium stearate 200.0029.009.0015.0010.5029.006.001.50 Active ingredient diluents and disintegrants Disintegrants Absorption enhancers Binders Diluents and disintegrants Disintegrants Lubricants

[0143] Carry out the Visulution of the tablet in 0.01N HCL for 2 hours, then carry out in phosphate buffer (pH 6.8) until the tablet disintegrates completely, the vision time in the buffer is 15 minutes.

Example 8: Tablet formulation comprising enteric coating of sodium caprate

[0144] An enteric-coated tablet formulation comprising sodium caprate was prepared according to the following table:

component Feeding amount/tablet (mg) function Intragranular [2-(8,9-dioxo-2,6-diazabicyclo[5.2.0]non-1(7)-en-2-yl)ethyl]phosphate microcrystalline cellulose (AVICEL PH101) Croscarmellose Sodium Caprate Sodium Povidone USP, 17PF 200.0020.0020.0050.0018.00 Active ingredient diluents and disintegrants Disintegrants Absorption enhancers Binders component Feeding amount/tablet (mg) function Extragranular Microcrystalline Cellulose (AVICEL PH101) Croscarmellose Sodium Magnesium Stearate 82.008.002.00 Diluents and Disintegrants Disintegrants Lubricants

Example 9: Tablet formulation comprising enteric coating and capsule formulation of palmitoylcarnitine

[0145] The capsule formulation comprising enteric-coated tablet formulation and palmitoylcarnitine was prepared according to the following table:

component %(W/W) mg/tablet Intragranular [2-(8,9-dioxo-2,6-diazabicyclo[5.2.0]non-1(7)-en-2-yl)ethyl]phosphate cross-linked carboxymethyl fiber Sodium povidone USP, 17PF granule externally linked carboxymethyl cellulose sodium microcrystalline cellulose (AVICEL PH101) magnesium stearate 86.753.061.532.046.110.51 200.007.053.534.7014.101.18 Tablet weight 100.00 230.56 Enteric film coating weight 8.00 18.44 final film weight 249.00 Palmitoyl Carnitine HGC#1 2001 capsules (TIC)

Example 10:

Bioavailability of [2-(8,9-dioxo-2,6-diazabicyclo[5.2.0]non-1(7)-en-2-yl)ethyl]phosphate in Beagle dogs : Evaluation of oral formulations

[0146] This study set out to [2-8,9-dioxo-2,6-diazabicyclo[5.2.0]non-1(7)-en-2-yl)ethyl]phosphoric acid in The bioavailability in Beagle dogs was studied. The comparison of test formulations included immediate-release capsule formulations and 7 enteric-coated formulations.

[0147] Twelve female Beagle dogs were divided into four groups (3/group). The study included a two-week crossover study. Each treatment was separated by a one-week washout period. Each group was given a single dose of 200 or 400 mg of [2-(8,9-dioxo-2,6-diazabicyclo[5.2.0]non-1(7)-en-2-yl)ethyl] phosphoric acid.

[0148] All formulations were administered with 10 ml of water. Blood samples were collected by jugular vein puncture at times specified in the protocol; plasma was separated, frozen and stored at -70°C until analysis. Determination of [2-(8,9-dioxo-2,6-diazabicyclo[5.2.0]non-1(7)-en-2-yl)ethyl]phosphoric acid concentration by validated HPLC analysis .

To plasma [2-(8,9-dioxo-2,6-diazabicyclo[5.2.0] non-1(7)-en-2-yl) ethyl] phosphoric acid concentration-time The curves were subjected to non-compartmental analysis. C _max and t _max values were recorded directly from individual dog curves and AUC (0-24) values were calculated using the linear trapezoidal method. The results are shown in Table 3.

[0150] The results show that enteric-coated formulations containing absorption enhancers provide greater [2-(8,9-dioxo-2,6-di Exposure of azabicyclo[5.2.0]non-1(7)-en-2-yl)ethyl]phosphoric acid. The results also showed that enteric-coated formulations containing absorption enhancers provided greater [2-(8,9-dioxo-2 , exposure of 6-diazabicyclo[5.2.0]non-1(7)-en-2-yl)ethyl]phosphoric acid. The mean dose-normalized ratio (AUC _0-24 ) of the enteric-coated formulations to the immediate-release capsules ranged from 1.20 to 2.51.

table 3 preparation absorption enhancer AUC _0-24 (μg?·hr/mL) AUC ^ratioa C _max (μg/mL) C _max ratio ^a t _max (hours) T _lag (hours) 2 x 200mg immediate release capsules (comparison) (Example 2) none 18.6(6.17) - 6.20 (4.53) - 1.33(0.76) 0 1×200mg enteric-coated tablet (comparison) none 5.24 (5.06) 0.56 2.55(2.34) 0.82 2.50(1.50) 0.83(0.58) 2×200mg enteric-coated tablets (comparison) none 22.3(9.14) 1.20 12.7(6.89) 2.04 2.67(1.15) 1.67(0.76) 2×200mg enteric-coated tablets Polyethylene glycol-20 sorbitan monooleate (TWEEN-80) 24.0(14.0) 1.29 14.5(9.30) 2.34 1.67 (1.15) 0.67(1.15) 2×200mg enteric-coated tablets Sodium dodecyl sulfate 36.9 (31.4) 1.98 17.6(16.2) 2.84 1.00(0.00) 0 2×200mg enteric-coated tablets sodium caprate 46.7 (28.9) 2.51 24.8(20.4) 4.00 1.67 (1.26) 0.17(0.29) 2×200mg enteric-coated tablets EDTA 24.6(14.1) 1.32 13.5(9.99) 2.18 2.17 (1.61) 1.18(0.75) 2×200mg enteric-coated tablets palmitoylcarnitine 29.5(25.9) 1.59 15.5(16.4) 2.51 2.50(1.32) 1.17 (2.02)

a: mean of dose-normalized ratios for immediate-release capsules

Example 11:

Pharmacokinetic study of a single dose of 2-(8,9-dioxo-2,6-diazabicyclo[5.2.0]non-1(7)-en-2-yl)ethyl]phosphate

[0151] A tolerability study of ascending single doses was performed with oral doses of 500, 1000, 2000, and 4000 mg administered fasted. In each group, 8 subjects received either placebo (2 subjects) or the prescribed dose of 2-(8,9-dioxo-2,6-diazabicyclo[5.2.0] non-1(7)-en-2-yl)ethyl]phosphate (6 subjects). During cycle 2 of the study, subjects in the fasted 1000 mg group crossed over to receive a 1000 mg postprandial dose. Additionally, the 2000 mg dose level was repeated in the group of elderly subjects.

Table 4 summarizes the oral administration of 2-(8,9-dioxo-2,6-diazabicyclo[5.2.0]non-1(7)-ene in the fasted state for all groups in this study -2-yl)ethyl]phosphoric acid capsules after the pharmacokinetic curves. 2-(8,9-Dioxo-2,6-diazabicyclo[5.2.0]non-1(7)-en-2-yl)ethyl]phosphate was rapidly eliminated within 1 to 2 hours after application Absorption reaches peak plasma concentration. Plasma concentrations of 2-(8,9-dioxo-2,6-diazabicyclo[5.2.0]non-1(7)-en-2-yl)ethyl]phosphate subsequently decreased and its elimination as mono Exponential or occasionally double-exponential elimination has an average t _1/2 of 6 to 16 hours, but estimates of t _1/2 are not always reliable. For the first group of subjects, the mean absolute bioavailability was estimated to be 4.3%.

[0153] For the second group of subjects, 2-(8,9-dioxo-2,6-diazabicyclo[5.2.0]nonane-1( 7)-en-2-yl)ethyl]phosphoric acid delays 2-(8,9-dioxo-2,6-diazabicyclo[5.2.0]non-1(7)-en-2-yl ) ethyl]phosphate, prolonging the mean t _max by about 2 hours (from 0.88 to 2.92 hours) and reducing the mean C _max by 67% (from 1179 to 392 ng/ml). In addition, administration with food reduces the mean AUC 57% (from 5132 to 2210 ng·h/mL).

[0154] In elderly subjects receiving 2000 mg of 2-(8,9-dioxo-2,6-diazabicyclo[5.2.0]non-1(7)-en-2yl)ethyl]phosphoric acid In subjects (fasting, single dose), mean oral administration clearance (Cl/F) was approximately 10% lower than in healthy adult subjects receiving the same dose (3.14 vs 3.50 L/h/kg). Therefore, the 2-(8,9-dioxo-2,6-diazabicyclo[5.2.0]non-1(7)-en-2-yl)ethyl]phosphate in elderly subjects The average AUC was slightly higher (8891 vs. 7644ng·h/mL).

Table 4

2-(8,9-dioxo-2,6-diazabicyclo[5.2.0]nonan-1(7)-

Mean ± SD (%CV) of PK parameters of en-2-yl) ethyl] phosphate (n = 6 for each group) dose C _max (ng/mL) T _max (h) T _1/2 (h) AUC _0-24 (ng h/mL) 500mg orally, fasting 320±63(20%) 1.9±0.7(39%) 6.7±6.4 (96%) 2140±542(25%) 100mg 1-hour, injection 4007±512 (13%) 0.95±0.11(12%) 8.3±8.8(106%) 10226±1719 (17%) 1000mg orally, fasting 1179±618 (52%) 0.88±0.59(67%) 14.6±9.3 (64%) 5132±1420 (28%) 1000mg orally, with food 392±236 (60%) 2.92±1.20 (41%) 16.0±10.0(63%) 2210±578 (26%) 2000mg orally, fasting 1786±1364 (76%) 1.42±0.96(68%) 6.4±2.0 (32%) 7644±1828(25%) 2000mg orally, fasting (elderly) 1606±628 (39%) 1.25±0.61 (49%) 14.1±11.1 (79%) 8891±1437(16%) 4000mg orally, fasting 1488±436 (29%) 2.60±1.08(42%) 9.1±4.6 (51%) 8982±1981 (22%)

AUC reported in Table 4 for t = 0 to ∞

Example 12:

Pharmacokinetics of multiple doses of [2-(8,9-dioxo-2,6-diazabicyclo[5.2.0]non-1(7)-en-2-yl)ethyl]phosphate Research

[0155] Carried out [2-(8,9-dioxo-2,6-diazabicyclo[5.2.0]non-1(7)-en-2-yl)ethyl]phosphoric acid In a multiple-dose tolerance study, oral doses of 200, 400, 800, and 1600 mg were administered to healthy subjects in 14-day cycles.

[0156] Table 5 describes the pharmacokinetic data after multiple ascending doses. Figures 1 to 6 are shown below:

Figure 1 shows the results of receiving 200, 400, 800 or 1600 mg of [2-(8,9-dioxo-2,6-diazabicyclo[5.2.0]non-1(7)-en-2-yl ) Alkyl] phosphoric acid in healthy subjects as a function of time (hours) after a single dose of [2-(8,9-dioxo-2,6-diazabicyclo[5.2.0]nonane-1( 7) Mean plasma concentration (ng/mL) curve of -en-2-yl)alkyl]phosphate.

Fig. 2 is after receiving 200, 400, 800, or 1600 mg of [2-(8,9-dioxo-2,6-diazabicyclo[5.2.0]non-1(7)-ene-2- A single dose of [2-(8,9-dioxo-2,6-diazabicyclo[5.2.0]nonane-1 C _max (ng/mL) curve of (7)-en-2-yl)alkyl]phosphoric acid.

Fig. 3 is after receiving 200, 400, 800, or 1600 mg of [2-(8,9-dioxo-2,6-diazabicyclo[5.2.0]non-1(7)-ene-2- A single dose of [2-(8,9-dioxo-2,6-diazabicyclo[5.2.0]nonane-1 AUC (ng·h/mL, t=0 to ∞) curve of (7)-en-2-yl)alkyl]phosphoric acid.

Fig. 4 is in receiving 200,400,800, or 1600mg [2-(8,9-dioxo-2,6-diazabicyclo[5.2.0]non-1(7)-ene-2- [2-(8,9-dioxo-2,6-diazabicyclo[5.2.0]nonan-1(7 )-en-2-yl)alkyl]phosphate mean steady-state plasma concentration (ng/mL) curve.

Fig. 5 is after receiving 200, 400, 800, or 1600 mg of [2-(8,9-dioxo-2,6-diazabicyclo[5.2.0]non-1(7)-ene-2- [2-(8,9-dioxo-2,6-diazabicyclo[5.2.0]nonan-1(7 Steady-state C _max (ng/mL) curve of )-en-2-yl)alkyl]phosphoric acid.

Figure 6 receives 200, 400, 800, or 1600mg of [2-(8,9-dioxo-2,6-diazabicyclo[5.2.0]non-1(7)-en-2-yl [2-(8,9-dioxo-2,6-diazabicyclo[5.2.0]nonane-1(7) Steady-state AUC (ng·h/mL) curve of -en-2-yl)alkyl]phosphoric acid.

table 5

In healthy subjects [2-(8,9-dioxo-2,6-diazabicyclo[5.2.0]non-1(7)-en-2-yl)

Mean ± SD (%CV) of ethyl] phosphate PK parameters (n=6 for each group) dose C _max (ng/mL) T _max (h) T _1/2 (h) AUC ^** (ng h/mL) Single dose administration 200 mg orally, fasting 172±90 (52%) 1.3±0.5(40%) 3.5±0.6(18%) 699±201 (29%) 400mg orally, fasting 346±282 (82%) 2.0±1.6(79%) 4.5±1.2 (27%) 1487±371(25%) 800mg orally, fasting 715±524 (73%) 1.4±0.7(47%) 8.3±1.3(16%) 3188±800(25%) 1600mg orally, fasting 962±592 (62%) 1.3±1.3(98%) 6.9±1.7 (24%) 4057±1316 (32%) Multiple dose administration (14 days) 200mg q 12h orally, with food 153±75 (49%) 1.2±0.3(27%) 6.6±3.9(60%) 817±265 (32%) 400mg q 12h orally, fasting 398±209 (53%) 1.6±1.3 (83%) 11.9±10.4 (87%) 1811±747 (41%) 800mg q 12h orally, fasting 436±151 (35%) 1.4±0.6(40%) 16.9±8.8 (52%) 2175±644(30%) 1600mg q 12h orally, fasting 1509±842 (56%) 1.4±1.3(90%) 10.5±6.6 (63%) 4909±1211 (25%)

AUC reported in Table 5 for single dose administration from t=0 to ∞

Reported AUC for multiple dose administration from t=0 to 12 hours (tau)

[0157] Where ranges for physical properties, such as molecular weight, or ranges for chemical properties, such as chemical formulas, are used herein, all combinations and subcombinations of ranges are intended to be encompassed therein.

[0158] The disclosures of each patent, patent application and publication cited or described in this document are hereby incorporated by reference in their entirety.

[0159] Those skilled in the art will recognize that many changes and modifications can be made to the preferred embodiments of the invention and that such changes and modifications can be made without departing from the spirit of the invention. Accordingly, the appended claims are intended to cover all such equivalent changes as fall within the true spirit and scope of the invention.

Claims (108)

1. solid pharmaceutical dosage formulation comprises:

The chemical compound of at least a formula (I) or its pharmaceutically acceptable salt:

Wherein:

R ₁Be hydrogen, C ₁To C ₆Alkyl, C ₂To C ₇Acyl group, C ₁To C ₆The alkane sulfonyl, or C ₆To C ₁₄Aroyl;

A is the alkylidene of 1 to 4 carbon atom or the alkenylene of 2 to 4 carbon atoms;

R ₂And R ₃Independently be selected from hydrogen,

Condition is R ₂And R ₃Have at least one not to be hydrogen;

R ₄And R ₅Be independently selected from hydrogen, C ₁To C ₄Alkyl, C ₅To C ₇Aryl, have the C of 5 to 7 carbon atoms on the aromatic ring ₆To C ₁₅Aralkyl, C ₂To C ₇Thiazolinyl, or C ₂To C ₇Alkynyl, or R ₄And R ₅Can form spiral shell C jointly ₃To C ₈Carbocyclic ring;

R ₆Be C ₁To C ₁₂The alkyl of straight or branched, C ₂To C ₇The alkenyl or alkynyl of straight or branched, C ₅To C ₁₃Aryl, partly have the C of 5 to 13 carbon atoms at aromatic ring ₆To C ₂₁Aralkyl, 5 yuan to 13 yuan heteroaryl has 6 yuan to 21 yuan heteroarylalkyl of 5 to 13 atoms, C on heteroaryl moieties ₄To C ₈Cycloalkyl, have the C of 4 to 8 carbon atoms at cycloalkyl ring ₅To C ₁₆Cycloalkyl-alkyl;

R ₇And R ₈Be independently selected from hydrogen, C ₁To C ₁₂The alkyl of straight or branched, C ₂To C ₇The alkenyl or alkynyl of straight or branched, C ₅To C ₁₃Aryl, have the C of 5 to 13 carbon atoms at aryl moiety ₆To C ₂₁Aralkyl, 5 yuan to 13 yuan heteroaryl has 6 yuan to 21 yuan heteroarylalkyl of 5 to 13 atoms or R at heteroaryl moieties ₇And R ₈Can form jointly and have 4 to 8 carbon atoms on the ring and randomly be selected from nitrogen, the cycloalkyl of one or two atom or Heterocyclylalkyl in oxygen or the sulfur;

Wherein has aryl, heteroaryl, arbitrary R of cycloalkyl or Heterocyclylalkyl part ₁To R ₈Group can be chosen wantonly at aryl, heteroaryl, and cycloalkyl or Heterocyclylalkyl part independently are selected from halogen, cyano group, nitro or hydroxyl, C by 1 to about 5 ₁To C ₆Alkyl, C ₁To C ₆The substituent group of alkoxyl replace; With

At least a pharmaceutically acceptable absorption enhancer.

2. solid pharmaceutical dosage formulation comprises:

The chemical compound of at least a general formula (I) or its pharmaceutically acceptable salt:

Wherein:

R ₁Be hydrogen;

A is-(CH ₂) _n-, n is 2; With

R ₂And R ₃Be hydrogen; With

At least a pharmaceutically acceptable absorption enhancer.

3. according to the dosage form of claim 1 or 2, it is a powder, capsule or tablet.

4. according to the dosage form of claim 1 or 2, it is the capsule of enteric coating or the tablet of enteric coating.

5. according to the dosage form of claim 4, it comprises and is selected from methacrylic acid copolymer, cellulose acetate phthalate, hydroxypropylmethyl cellulose phthalate, polyvinyl acetate phthalate, Lac, hydroxypropyl methyl cellulose succinate, the anionic polymer of carboxymethyl cellulose.

6. according to the dosage form of claim 1 or 2, it is instant-free capsule or immediate release tablet.

7. according to the dosage form of claim 1 or 2, it comprises the chemical compound of about 25% weight to the described formula (I) of about 99.5% weight, in the gross weight of described dosage form.

8. according to the dosage form of claim 7, it comprises the chemical compound of about 50% weight to the described formula (I) of about 99.5% weight, in the gross weight of described dosage form.

9. dosage form according to Claim 8, it comprises the chemical compound of about 60% weight to the described formula (I) of about 99.5% weight, in the gross weight of described dosage form.

10. according to the dosage form of claim 9, it comprises the chemical compound of about 70% weight to the described formula (I) of about 99.5% weight, in the gross weight of described dosage form.

11. according to the dosage form of claim 1, wherein R ₁Be hydrogen or C ₁To C ₄Alkyl.

12. according to each dosage form in claim 1 or the claim 3 to 11, wherein A has formula-(CH ₂) _n-alkylidene, wherein n is 1 to 3.

13. according to each dosage form in claim 1 or the claim 3 to 12, wherein R ₂Be hydrogen.

14. according to each dosage form in claim 1 or the claim 3 to 13, wherein R ₄And R ₅Be hydrogen independently, C ₁To C ₄Alkyl, and R ₆Be C ₃To C ₁₀The alkyl of straight or branched, C ₅To C ₇Aryl, 5 yuan to 7 yuan heteroaryl has the cycloalkyl of 5 to 7 carbon atoms on ring.

15. according to the dosage form of claim 14, wherein R ₆Be C ₅To C ₇Aryl.

16. according to each dosage form in the claim 1 to 15, wherein R ₂And R ₃All be hydrogen.

17. according to the dosage form of claim 1, the chemical compound of wherein at least a described formula (I) is:

3-{2-[8,9-dioxo-2,6-diazabicyclo [5.2.0] ninth of the ten Heavenly Stems-1 (7)-alkene-2-yl] ethyl }-3-epoxy-7-oxo-7-phenyl-2,4,6-trioxa-3-phospha seven-1-yl benzoic acid ester;

3-{2-[8,9-dioxo-2,6-diazabicyclo [5.2.0] ninth of the ten Heavenly Stems-1 (7)-alkene-2-yl] ethyl }-3-epoxy-7-oxo-8-propyl group-2,4,6-trioxa-3-phospha 11-1-base 2-Propylpentanoic ester;

2, and 2-dimethyl-propanoic acid (2,2-dimethyl-propionyloxy methoxyl group-[2-(8,9-dioxo-2,6-diaza-dicyclo [5.2.0] ninth of the ten Heavenly Stems-1 (7)-alkene-2-yl)-ethyl]-phosphine oxygen ylmethyl ester;

7-cyclohexyl-3-{2-[8,9-dioxo-2,6-diazabicyclo [5.2.0] ninth of the ten Heavenly Stems-1 (7)-alkene-2-yl] ethyl }-1,5-dimethyl-3-epoxy-7-oxo-2,4,6-trioxa-3-phospha seven-1-basic ring cyclohexane carboxylic-acid ester;

7-cyclohexyl-3-{2-[8,9-dioxo-2,6-diazabicyclo [5.2.0] ninth of the ten Heavenly Stems-1 (7)-alkene-2-yl] ethyl }-3-epoxy-7-oxo-2,4,6-trioxa-3-phospha seven-1-basic ring cyclohexane carboxylic-acid ester;

[2-(8,9-dioxo-2,6-diaza-dicyclo [5.2.0] ninth of the ten Heavenly Stems-1-(7)-alkene-2-yl)-ethyl]-di(2-ethylhexyl)phosphate isopropoxy carbonyl oxygen ylmethyl ester;

[2-[8,9-dioxo-2,6-diazabicyclo [5.2.0] ninth of the ten Heavenly Stems-1 (7)-alkene-2-yl] ethyl]-two [1-(benzoyloxy group) ethyl] esters of phosphoric acid;

Benzoic acid [2-(8,9-dioxo-2,6-diaza-dicyclo [5.2.0] ninth of the ten Heavenly Stems-1 (7)-alkene-2-yl)-ethyl]-hydroxyl-phosphine oxygen ylmethyl ester; With

[2-(8,9-dioxo-2,6-diaza-dicyclo [5.2.0] ninth of the ten Heavenly Stems-1 (7)-alkene-2-yl)-ethyl]-di(2-ethylhexyl)phosphate dimethyl methyl aminoacyl methoxyl group ester;

Or its pharmaceutically acceptable salt.

18. according to each dosage form in the claim 1 to 17, it comprises the described absorption enhancer of about 0.25% weight to about 50% weight, in the gross weight of described dosage form.

19. according to each dosage form in the claim 1 to 18, wherein pharmaceutically acceptable absorption enhancer is a surfactant, cholate, fatty acid, soap, chelating agent, acylcarnitines, acyl group choline or its mixture.

20. according to the dosage form of claim 19, wherein surfactant is an ionic surfactant, nonionic surfactant or and composition thereof.

21. according to the dosage form of claim 20, wherein said ionic surfactant is a sodium lauryl sulphate, aerosol OT or its mixture.

22. according to the dosage form of claim 20, wherein said nonionic surfactant is a polyoxyethylene alkyl ether, polyxyethylated ester, polysorbate or its mixture.

23. according to the dosage form of claim 22, wherein said polyoxyethylene alkyl ether is Polyethylene Glycol-20 sorbitan monooleate

24. according to the dosage form of claim 19, wherein said cholate is a sodium cholate, sodium deoxycholate or its mixture.

25. according to the dosage form of claim 19, wherein fatty acid is an oleic acid.

26. according to the dosage form of claim 19, wherein soap is Capric acid sodium salt.

27. according to the dosage form of claim 19, wherein said chelating agent is an ethylenediaminetetraacetic acid.

28. according to the dosage form of claim 19, wherein said is the acylcarnitines palmitoyl carnitine.

29. according to the dosage form of claim 19, wherein the acyl group choline is the lauroyl choline.

30. according to each dosage form in the claim 1 to 29, it further comprises filler, disintegrating agent, binding agent, lubricant or and composition thereof.

31. according to the dosage form of claim 30, wherein said filler is a lactose, microcrystalline Cellulose, mannitol, calcium phosphate, pregelatinized Starch, pregelatinated sucrose or and composition thereof.

32. according to the dosage form of claim 30, wherein said disintegrating agent is cross-linked carboxymethyl cellulose sodium, starch, carboxymethyl starch sodium, pregelatinized Starch, polyvinylpolypyrrolidone and composition thereof.

33. according to the dosage form of claim 30, wherein said binding agent is a polyvidone, hydroxypropyl emthylcellulose, polyvinyl alcohol, gelatin, natural gum and composition thereof.

34. according to the dosage form of claim 30, wherein said lubricant is a magnesium stearate, sodium stearyl fumarate and composition thereof.

35. the single dose form comprises in the claim 1 to 34 each dosage form.

36. the multiple dose form comprises in the claim 1 to 34 each dosage form.

37. at least a method that is selected from the disease of cerebrovascular disease of treatment in mammal, described disease is selected from cerebral ischemia, cerebral infarction or cerebral vasospasm; Cerebral trauma; Muscular spasm; Be selected from the convulsive disorder of epilepsy or status epilepticus; Hypoglycemia; Asystole; Perinatal asphyxia disease; Or chorda dorsalis injury, comprise step:

Give have the Orally administered effective dose of mammal that needs according to each dosage form in the claim 1 to 36.

38. at least a method that is selected from the disease of glaucoma or diabetes end-organ complication of treatment in mammal comprises step:

Give have the Orally administered effective dose of mammal that needs according to each dosage form in the claim 1 to 36.

39. at least a anxiety disorder that is selected from of treatment in mammal; Mood disorders; Schizophrenia; Schizophreniform disorder; Or the method for the disease of schizoaffective disorder, comprise step:

Give have the Orally administered effective dose of mammal that needs according to each dosage form in the claim 1 to 36.

40. as the method for claim 39, wherein anxiety disorder is selected from panic attack, agoraphobia, panic disorder, specific phobia, social phobia, obsessive compulsive disorder, posttraumatic stress disorder, acute stress disorder, generalized anxiety disorder, separation anxiety disorder, or the anxiety disorder that causes of material; Or mood disorders is selected from bipolar disorder, is selected from major depressive disorder, the dysthymic disorder, and the depression of the mood disorders of or material-cause, or be selected from the severe depression outbreak, manic episode, Combination outbreak, or the outbreak of the emotion of hypomania.

41. at least a Huntington's disease that is selected from of treatment in mammal, Alzheimer, amyotrophic lateral sclerosis, chronic dementia, or the method for the neurodegenerative disease of cognitive impairment comprise step:

Give have the Orally administered effective dose of mammal that needs according to each dosage form in the claim 1 to 36.

42. treat Parkinsonian method, comprise step:

Give have the Orally administered effective dose of mammal that needs according to each dosage form in the claim 1 to 36.

43. at least a inflammatory diseases that is selected from of treatment in mammal; Fibromyalgia; The herpes zoster complication; The prevention of the tolerance of OA; Or the method for the disease of the withdrawal symptom of addictive drug, comprise step:

Give have the Orally administered effective dose of mammal that needs according to each dosage form in the claim 1 to 36.

44. the method for treatment pain in mammal comprises step:

Give have the Orally administered effective dose of mammal that needs according to each dosage form in the claim 1 to 36.

45., further comprise at least a pain relief agents of administering therapeutic effective dose according to the method for claim 44.

46. according to the method for claim 44, wherein pain is neuropathic pain; Cancerous pain; With pancreatitis or abdominal part, pelvis or perineal region or relevant visceral pain; With back of the body bottom or top, spinal column, muscle fiber pain, the musculoskeletal pain that remporomandibular joint or myofasical pain syndrome are relevant; The boniness pain relevant with bone or degenerative joint disease; Headache; With infection, reaping hook cell anemia disease, autoimmune sexual disorders, multiple sclerosis, dental procedure, burn or the pain of inflammation-related at least a.

47. method according to claim 44, wherein pain comprise neuropathic pain and and diabetic neuropathy, peripheral neurophaty, postherpetic neuralgia, trigeminal neuralgia, waist or cervix uteri radiculopathy, fibromyalgia, glossopharyngeal neuralgia, reflex sympathetic dystrophy, causalgia, thalamic syndrome, nerve root avulsion, or by being selected from phantom limb pain, the nerve injury that the damage of reflex sympathetic dystrophy or thoracotomy postoperative pain causes, cancer, chemical injury, toxin, malnutrition, or at least a relevant in virus or the bacterial infection.

48. according to the method for claim 46, wherein said pain is the fine fibre neuropathy.

49. according to the method for claim 46, wherein said pain is big fiber nerve pathological changes.

50. according to the method for claim 46, wherein said pain is peripheral neurophaty.

51. according to the method for claim 46, wherein said pain is the nervus centralis disease.

52. according to the method for claim 46, wherein said pain is postherpetic neuralgia.

53. according to the method for claim 46, wherein said pain is postoperative pain.

54. solid instant-free pharmaceutical composition comprises:

At least a as claim 12 or claim 11 to 17 in chemical compound or its pharmaceutically acceptable salt of formula (I) of each definition,

Wherein said compositions has the 0.5g/cm of being at least about ³Bulk density.

55. according to the solid instant-free pharmaceutical composition of claim 54, wherein said compositions has the 0.8g/cm of being at least about ³Bulk density.

56. according to the solid instant-free pharmaceutical composition of claim 54 or 55, wherein said compositions is a granule.

57. according to each solid instant-free pharmaceutical composition of claim 54 to 56, wherein said compositions further comprises at least a binding agent.

58. according to the solid instant-free pharmaceutical composition of claim 57, wherein said binding agent is a polyvidone.

59. according to the solid instant-free pharmaceutical composition of claim 58, wherein said polyvidone exists with the level of 1.5% weight at least, in described composition total weight.

60. according to the solid instant-free pharmaceutical composition of claim 59, wherein said polyvidone exists with the level of 2.5% weight at least, in described composition total weight.

61. according to each solid instant-free pharmaceutical composition in the claim 54 to 60, wherein said compositions further comprises at least a disintegrating agent or filler.

62. according to the solid instant-free pharmaceutical composition of claim 61, wherein said filler is a microcrystalline Cellulose.

63. according to the solid instant-free pharmaceutical composition of claim 61, wherein said disintegrating agent is a cross-linking sodium carboxymethyl cellulose.

64. solid pharmaceutical dosage formulation comprises: according to each solid instant-free pharmaceutical composition in the claim 54 to 63.

65. according to the dosage form of claim 64, it is capsule or tablet.

66. the single dose form comprises the dosage form according to claim 64 or 65.

67. the multiple dose form comprises the dosage form according to claim 64 or 65.

68. capsule comprises: comprise granule according to each solid instant-free pharmaceutical composition in the claim 54 to 63.

69. tablet comprises: comprise granule according to each solid instant-free pharmaceutical composition in the claim 54 to 63.

70. at least a method that is selected from the disease of cerebrovascular disease of treatment in mammal, described disease is selected from cerebral ischemia, cerebral infarction or cerebral vasospasm; Cerebral trauma; Muscular spasm; Be selected from the convulsive disorder of epilepsy or status epilepticus; Hypoglycemia; Asystole; Perinatal asphyxia disease; Or chorda dorsalis injury, comprise step:

Give have the Orally administered effective dose of mammal that needs according to each solid instant-free pharmaceutical composition in the claim 54 to 63.

71. at least a method that is selected from the disease of glaucoma or diabetes end-organ complication of treatment in mammal comprises step:

Give have the Orally administered effective dose of mammal that needs according to each solid instant-free pharmaceutical composition in the claim 54 to 63.

72. at least a anxiety disorder that is selected from of treatment in mammal; Mood disorders; Schizophrenia; Schizophreniform disorder; Or the method for the disease of schizoaffective disorder, comprise step:

Give have the Orally administered effective dose of mammal that needs according to each solid instant-free pharmaceutical composition in the claim 54 to 63.

73. as the method for claim 72, wherein anxiety disorder is selected from panic attack, agoraphobia, panic disorder, specific phobia, social phobia, obsessive compulsive disorder, posttraumatic stress disorder, acute stress disorder, generalized anxiety disorder, separation anxiety disorder, or the anxiety disorder that causes of material; Or mood disorders is selected from bipolar disorder, is selected from major depressive disorder, the dysthymic disorder, and the depression of the mood disorders of or material-cause, or be selected from the severe depression outbreak, manic episode, Combination outbreak, or the outbreak of the emotion of hypomania.

74. at least a Huntington's disease that is selected from of treatment in mammal, Alzheimer, amyotrophic lateral sclerosis, chronic dementia, or the method for the neurodegenerative disease of cognitive impairment comprise step:

Give have the Orally administered effective dose of mammal that needs according to each solid instant-free pharmaceutical composition in the claim 54 to 63.

75. treat Parkinsonian method, comprise step:

Give have the Orally administered effective dose of mammal that needs according to each solid instant-free pharmaceutical composition in the claim 54 to 63.

76. at least a inflammatory diseases that is selected from of treatment in mammal; Fibromyalgia; The herpes zoster complication; The prevention of the tolerance of OA; Or the method for the disease of the withdrawal symptom of addictive drug, comprise step:

Give have the Orally administered effective dose of mammal that needs according to each solid instant-free pharmaceutical composition in the claim 54 to 63.

77. the method for treatment pain in mammal comprises step:

Give have the Orally administered effective dose of mammal that needs according to each solid instant-free pharmaceutical composition in the claim 54 to 63.

78., further comprise at least a pain relief agents of administering therapeutic effective dose according to the method for claim 77.

79. according to the method for claim 77, wherein pain is neuropathic pain; Cancerous pain; With pancreatitis or abdominal part, pelvis or perineal region or relevant visceral pain; With back of the body bottom or top, spinal column, muscle fiber pain, the musculoskeletal pain that remporomandibular joint or myofasical pain syndrome are relevant; The boniness pain relevant with bone or degenerative joint disease; Headache; With infection, reaping hook cell anemia disease, autoimmune sexual disorders, multiple sclerosis, dental procedure, burn or the pain of inflammation-related at least a.

80. method according to claim 79, wherein pain comprise neuropathic pain and and diabetic neuropathy, peripheral neurophaty, postherpetic neuralgia, trigeminal neuralgia, waist or cervix uteri radiculopathy, fibromyalgia, glossopharyngeal neuralgia, reflex sympathetic dystrophy, causalgia, thalamic syndrome, nerve root avulsion, or by being selected from phantom limb pain, the nerve injury that the damage of reflex sympathetic dystrophy or thoracotomy postoperative pain causes, cancer, chemical injury, toxin, malnutrition, or at least a relevant in virus or the bacterial infection.

81. according to the method for claim 79, wherein said pain is the fine fibre neuropathy.

82. according to the method for claim 79, wherein said pain is big fiber nerve pathological changes.

83. according to the method for claim 79, wherein said pain is peripheral neurophaty.

84. according to the method for claim 79, wherein said pain is the nervus centralis disease.

85. according to the method for claim 79, wherein said pain is postherpetic neuralgia.

86. according to the method for claim 79, wherein said pain is postoperative pain.

87. according to each solid instant-free pharmaceutical composition in the claim 54 to 63, wherein when the plasma C of the chemical compound of giving the formula (I) that described compositions table reveals when having the curee who needs to use _MaxFor about 80ng/mL to about 4200ng/mL.

88. according to each solid instant-free pharmaceutical composition in the claim 54 to 63, wherein as the blood plasma T of the chemical compound of giving the formula (I) that described compositions table reveals when having the curee who needs to use _MaxBe about 0.5 hour to about 4.0 hours.

89. according to each solid instant-free pharmaceutical composition in the claim 54 to 63, wherein as the AUC of the chemical compound of giving the formula (I) that described compositions table reveals when having the curee who needs to use _{T=0 to 12 hour}For about 250ngh/mL to about 6,000ngh/mL.

90. according to each solid instant-free pharmaceutical composition in the claim 54 to 63, wherein said compositions is the form of capsule or tablet.

91. according to the solid instant-free pharmaceutical composition of claim 90, wherein said capsule or tablet comprise the chemical compound of the formula (I) of about 200mg to 4000mg.

92. according to the solid instant-free pharmaceutical composition of claim 90, wherein said compositions is single dose unit or the unitary form of multiple dose.

93. according to the solid instant-free pharmaceutical composition of claim 92, wherein said single dose unit or multiple dose unit comprise the chemical compound of formula (I) of about 200mg or its pharmaceutically acceptable salt chemical compound or its pharmaceutically acceptable salt to the formula (I) of 4000mg.

94. according to the solid instant-free pharmaceutical composition of claim 93, wherein said single dose unit or multiple dose unit comprise chemical compound or its pharmaceutically acceptable salt of the formula (I) at least about 400mg.

95. according to the solid instant-free pharmaceutical composition of claim 93, wherein said single dose unit or multiple dose unit comprise chemical compound or its pharmaceutically acceptable salt of the formula (I) at least about 600mg.

96. method comprises step:

Form wet granular, it comprises:

At least a binding agent;

Randomly at least a filler;

Randomly at least a disintegrating agent; With

At least a as claim 1 or 2, or the chemical compound of the formula of each definition in the claim 11 to 17 (I) or its pharmaceutically acceptable salt; With

Form solid dosage forms.

97. according to the method for claim 96, wherein said wet granular passes through at least a filler or disintegrating agent and described formula (I) chemical compound or its pharmaceutically acceptable salt dry mixed; With the binder solution of at least a formation wet granular dry mixture is granulated then and form.

98. according to the method for claim 96, wherein said binding agent is a polyvidone.

99. according to the method for claim 96, wherein said filler is a microcrystalline Cellulose.

100. according to the method for claim 96, wherein said disintegrating agent is a sodium carboxymethyl cellulose.

101., further comprise step: dry described wet granular according to each method in the claim 96 to 100; The described dried granule of milling; Randomly the outer component of described dried granule of milling and one or more granules is mixed.

102. according to each method in the claim 96 to 101, wherein said solid dosage forms is a tablet.

103. according to each method in the claim 96 to 101, wherein said solid dosage forms is a capsule.

104. product by each method preparation in the claim 96 to 101.

105. the instant-free solid composite medicament of single dose unit or multiple dose unit form, comprise that [2-(8,9-dioxo-2,6-diazabicyclo [5.2.0] ninth of the ten Heavenly Stems-1 (7)-alkene-2-yl) alkyl] phosphoric acid or its pharmaceutically acceptable salt, the wherein plasma C of the chemical compound of the formula (I) that described compositions table reveals when using for the curee that needs are arranged _MaxFor about 80ng/mL to about 4200ng/mL.

106. the instant-free solid composite medicament of single dose unit or the unitary form of multiple dose, comprise that [2-(8,9-dioxo-2,6-diazabicyclo [5.2.0] ninth of the ten Heavenly Stems-1 (7)-alkene-2-yl) alkyl] phosphoric acid or its pharmaceutically acceptable salt, the AUC of the chemical compound of the formula (I) that described compositions table reveals when using for the curee that needs are arranged _{T=0 to 12 hour}For about 250ngh/mL to about 6,000ngh/mL.

107. the method for treatment pain, comprise that Orally administered [2-(8 to the mammal that needs are arranged, 9-dioxo-2,6-diazabicyclo [5.2.0] ninth of the ten Heavenly Stems-1 (7)-alkene-2-yl) alkyl] phosphoric acid or its pharmaceutically acceptable salt, its amount provide [2-(8,9-dioxo-2,6-diazabicyclo [5.2.0] ninth of the ten Heavenly Stems-1 (7)-alkene-2-yl) alkyl] plasma C of phosphoric acid _MaxFor about 80ng/mL to about 4200ng/mL.

108. the method for treatment pain, comprise that Orally administered [2-(8 to the mammal that needs are arranged, 9-dioxo-2,6-diazabicyclo [5.2.0] ninth of the ten Heavenly Stems-1 (7)-alkene-2-yl) alkyl] phosphoric acid or its pharmaceutically acceptable salt, its amount provide [2-(8,9-dioxo-2,6-diazabicyclo [5.2.0] ninth of the ten Heavenly Stems-1 (7)-alkene-2-yl) alkyl] AUC of phosphoric acid _{T=0 to 12 hour}For about 250ngh/mL to about 6,000ngh/mL.

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